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Thoughts about Dying in America: Enhancing the impact of one's life journey and legacy by also planning for the end of lifePROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAPizzo, P. A.2016; 113 (46): 12908-12912

Abstract

This Perspective offers a summary of the recommendations in the Institute of Medicine report Dying in America How we die is a deeply personal issue that each of us will face. However, the approach to end-of-life (EOL) care in the United States needs improvement. Too frequently, healthcare delivery is uncoordinated and has many providers who are not adequately prepared to have meaningful conversations about EOL planning. This is amplified by payment systems and policies that create impediments, misunderstanding, and sometimes misinformation. Dying in America made five recommendations to improve quality and honor individual preferences near the EOL beginning with making conversations with providers and families something that occurs during various phases of the life cycle and not just when one is facing serious illness or possible EOL. It was recommended (i) that public and private payers and care delivery organizations cover the provision of comprehensive care that is accessible and available to individuals on a 24/7 schedule; (ii) that professional societies and other entities establish standards for clinician patient communication and advance care planning and that payers and care delivery organizations adopt them; (iii) that educational institutions, credentialing bodies, accrediting boards, state regulatory agencies, and care delivery organizations establish palliative care training, certification, and/or licensure requirements; (iv) that public and private payers and care delivery organizations integrate the financing of health and social services; and (v) that public and private organizations should engage their constituents and provide fact-based information to encourage advance care planning and informed choice.

Infectiuos complications in children with cancer and children with human immunodeficiency virus infection.Clinical Approach to Infections in the Compromised HostAlexander SW, Mueller BU, Pizzo PA; in press

Children with immunodeficiencies.Infection Control in the Child Care Center and PreschoolPizzo PA; in press

Cytokines and biological response modifiers in the treatment of infection.management of Infectious Complications in Cancer PatientsPizzo PA, Mueller BU; in press

Fever and Neutropeniapractical Strategies in pediatric Diagnosis and TherapyPizzo PA; in press

American Pediatric Society's 2012 John Howland Award Lecture: pediatricians should be the model for the convergence of science and medicineAnnual Meeting of the Pediatric-Academic-SocietiesPizzo, P. A.NATURE PUBLISHING GROUP.2012: 324?28

Commentary: To Genotype or Not to Genotype? Addressing the Debate Through the Development of a Genomics and Personalized Medicine CurriculumACADEMIC MEDICINESalari, K., Pizzo, P. A., Prober, C. G.2011; 86 (8): 925-927

Abstract

As technologic innovation helps broaden and refine our knowledge base of genetic associations, a growing interest in translating these genetic discoveries to clinically useful laboratory tests has given rise to the potential of personalized medicine. To fully realize this potential, medical schools must educate trainees on genetic and genomic testing in clinical settings. An emerging debate in academic medical centers is not about the need for this education but, rather, the most effective educational models that should be deployed. At Stanford School of Medicine, several proposals to offer personal genotyping in the educational curriculum argued that learning genetics and the attendant cutting-edge molecular techniques would be more powerful and sustained if students were applying their knowledge to their personal genotypes. Given the complex ethical, legal, and social issues involved in implementing such a program, a schoolwide task force was formed to evaluate the risks and benefits of offering personal genotyping to students and residents. In this commentary, the authors discuss the salient issues raised by the task force and describe the safeguards adopted into the ultimate approval and implementation of the course, which included the opportunity for students to analyze their own genomes.

The changing face of febrile neutropenia-from monotherapy to moulds to mucositis. Where do we go from here?journal of antimicrobial chemotherapyPizzo, P. A.2009; 63: i16-7

Abstract

The initiation of monotherapy with a third- or fourth-generation cephalosporin, or with a carbapenem antibiotic, is now established medical practice for the neutropenic patient who becomes febrile. However, when the duration of neutropenia is prolonged (generally more than a week), additions to, or modifications of, the initial antibiotic regimen are necessary based on the evolving clinical and microbiological course of the patient. The rationale for these modifications of the initial therapy in high-risk neutropenic patients is reviewed along with the prospects for reducing the risk status of the neutropenic patient by bolstering or improving the host's immunological system and/or the time to haematological recovery.

Abstract

The coverage, cost, and quality problems of the U.S. health care system are evident. Sustainable health care reform must go beyond financing expanded access to care to substantially changing the organization and delivery of care. The FRESH-Thinking Project (www.fresh-thinking.org) held a series of workshops during which physicians, health policy experts, health insurance executives, business leaders, hospital administrators, economists, and others who represent diverse perspectives came together. This group agreed that the following 8 recommendations are fundamental to successful reform: 1. Replace the current fee-for-service payment system with a payment system that encourages and rewards innovation in the efficient delivery of quality care. The new payment system should invest in the development of outcome measures to guide payment. 2. Establish a securely funded, independent agency to sponsor and evaluate research on the comparative effectiveness of drugs, devices, and other medical interventions. 3. Simplify and rationalize federal and state laws and regulations to facilitate organizational innovation, support care coordination, and streamline financial and administrative functions. 4. Develop a health information technology infrastructure with national standards of interoperability to promote data exchange. 5. Create a national health database with the participation of all payers, delivery systems, and others who own health care data. Agree on methods to make de-identified information from this database on clinical interventions, patient outcomes, and costs available to researchers. 6. Identify revenue sources, including a cap on the tax exclusion of employer-based health insurance, to subsidize health care coverage with the goal of insuring all Americans. 7. Create state or regional insurance exchanges to pool risk, so that Americans without access to employer-based or other group insurance could obtain a standard benefits package through these exchanges. Employers should also be allowed to participate in these exchanges for their employees' coverage. 8. Create a health coverage board with broad stakeholder representation to determine and periodically update the affordable standard benefit package available through state or regional insurance exchanges.

Case Study: The Stanford University School of Medicine and Its Teaching HospitalsACADEMIC MEDICINEPizzo, P. A.2008; 83 (9): 867-872

Abstract

There is wide variation in the governance and organization of academic health centers (AHCs), often prompted by or associated with changes in leadership. Changes at AHCs are influenced by institutional priorities, economic factors, competing needs, and the personality and performance of leaders. No organizational model has uniform applicability, and it is important for each AHC to learn what works or does not on the basis of its experiences. This case study of the Stanford University School of Medicine and its teaching hospitals--which constitute Stanford's AHC, the Stanford University Medical Center--reflects responses to the consequences of a failed merger of the teaching hospitals and related clinical enterprises with those of the University of California-San Francisco School of Medicine that required a new definition of institutional priorities and directions. These were shaped by a strategic plan that helped define goals and objectives in education, research, patient care, and the necessary financial and administrative underpinnings needed. A governance model was created that made the medical school and its two major affiliated teaching hospitals partners; this arrangement requires collaboration and coordination that is highly dependent on the shared objectives of the institutional leaders involved. The case study provides the background factors and issues that led to these changes, how they were envisioned and implemented, the current status and challenges, and some lessons learned. Although the current model is working, future changes may be needed to respond to internal and external forces and changes in leadership.

Abstract

Industry's interaction with academia has created vast opportunity for innovation but also the potential for undue financial influence. Potential conflicts of interest can occur at the level of the individual researcher or the institution. Implementing guidelines and policies on conflicts of interest can help maintain appropriate separation between academic medicine and industry while permitting medical innovation to proceed. In an effort to retain public trust, Stanford University School of Medicine has enacted policies to identify and manage potential conflicts among its faculty, to divest of holdings in companies conducting studies involving Stanford investigators, and to ban all industry marketing and gifts from Stanford facilities.

Abstract

To update the 2000 American Society of Clinical Oncology guideline on the use of hematopoietic colony-stimulating factors (CSF).The Update Committee completed a review and analysis of pertinent data published from 1999 through September 2005. Guided by the 1996 ASCO clinical outcomes criteria, the Update Committee formulated recommendations based on improvements in survival, quality of life, toxicity reduction and cost-effectiveness.The 2005 Update Committee agreed unanimously that reduction in febrile neutropenia (FN) is an important clinical outcome that justifies the use of CSFs, regardless of impact on other factors, when the risk of FN is approximately 20% and no other equally effective regimen that does not require CSFs is available. Primary prophylaxis is recommended for the prevention of FN in patients who are at high risk based on age, medical history, disease characteristics, and myelotoxicity of the chemotherapy regimen. CSF use allows a modest to moderate increase in dose-density and/or dose-intensity of chemotherapy regimens. Dose-dense regimens should only be used within an appropriately designed clinical trial or if supported by convincing efficacy data. Prophylactic CSF for patients with diffuse aggressive lymphoma aged 65 years and older treated with curative chemotherapy (CHOP or more aggressive regimens) should be given to reduce the incidence of FN and infections. Current recommendations for the management of patients exposed to lethal doses of total body radiotherapy, but not doses high enough to lead to certain death due to injury to other organs, includes the prompt administration of CSF or pegylated G-CSF.

Abstract

Two multinational organizations, the Immunocompromised Host Society and the Multinational Association for Supportive Care in Cancer, have produced for investigators and regulatory bodies a set of guidelines on methodology for clinical trials involving patients with febrile neutropenia. The guidelines suggest that response (i.e., success of initial empirical antibiotic therapy without any modification) be determined at 72 h and again on day 5, and the reasons for modification should be stated. Blinding and stratification are to be encouraged, as should statistical consideration of trials specifically designed for showing equivalence. Patients enrolled in outpatient studies should be selected by use of a validated risk model, and patients should be carefully monitored after discharge from the hospital. Response and safety parameters should be recorded along with readmission rates. If studies use these guidelines, comparisons between studies will be simpler and will lead to further improvements in patient therapy.

Abstract

For over 30 years, fever and neutropenia in cancer patients has been treated with the utmost urgency, necessitating inpatient evaluation and immediate initiation of empirical broad-spectrum parenteral (i.v.) antibiotics. This practice is based on the recognition that delays in starting antibiotic therapy in febrile neutropenic patients have been associated with life-threatening infections and sometimes fatal consequences. Over the past decade, it has become evident that neutropenic cancer patients are not a homogeneous group and that practice guidelines may vary on their risk status. In fact, attempts have been made to stratify patients into high-risk and low-risk groups and differentiate treatment options respectively. Recent studies suggest that those neutropenic cancer patients who are at low risk may even be successfully treated with oral therapy, thus opening the possibility for ambulatory or home-based management. Oral antibiotic therapy, especially if safely delivered at home, offers a number of advantages including lower cost, improved quality of life (although the impact of shifting the burden of care from the hospital to the home setting on the patient, parent or care provider needs careful assessment) and a decreased risk for nosocomial infection.

Abstract

Early assessment of antiretroviral drug efficacy is important for prevention of the emergence of drug-resistant virus and unnecessary exposure to ineffective drug regimens. Current US guidelines for changing therapy are based on measurements of plasma HIV-1 RNA concentrations 4 or 8 weeks after the start of treatment with cut-off points of 0.75 or 1.00 log, respectively. We investigated the possibility of assessing drug efficacy from measurements of plasma HIV-1 concentrations made during the first week on therapy.The kinetics of virus decay in plasma during the first 12 weeks of treatment was analysed for 124 HIV-1-infected patients being treated for the first time with a protease inhibitor. Patients with a continuous decline of HIV-1 concentrations and in whom HIV-1 was either undetectable or declined by more than 1.5 log at 12 weeks were defined as good responders; the rest were poor responders.The individual virus decay rate constants (k) at day 6 correlated significantly (r>0.66, p<0.0001) with changes in HIV-1 concentrations at 4, 8, and 12 weeks, and correctly predicted 84% of the responses with a cut-off value of k=0.21 per day (in log scale). Reduction in plasma HIV-1 of less than 0.72 log by day 6 after initiation of therapy predicted poor long-term responses in more than 99% of patients.These results suggest that changes in HIV-1 concentration at day 6 after treatment initiation are major correlates of longer-term virological responses. They offer a very early measure of individual long-term responses, suggesting that treatment could be optimised after only a few days of therapy.

Abstract

This study investigated whether immune restoration occurred in 26 human immunodeficiency virus (HIV) type 1-infected children treated first with indinavir for 16 weeks and then with combination antiretroviral therapy for >2 years. Compared with baseline, a significant, although modest, decrease in virus loads (maximum median, -0.86 log(10)) and increase in the number of CD4(+) lymphocytes, especially naive cells, were observed at several time points after 2 years. A maximum of 7% of treated children achieved undetectable viremia. There was a marked increase in the proliferative response and skin reactivity to recall antigens. However, responses to an HIV antigen remained depressed, and the production of interleukin-12 remained unchanged and abnormally low. The magnitude of virus suppression did not correlate with these measures of functional immune reconstitution. These findings suggest that long-term nonsuppressive antiretroviral therapy can induce limited improvement in immune function in pediatric AIDS patients and that the effect of suppressive treatments should be investigated.

Abstract

To examine work-family balance issues and predictors of stress related to work-family balance among pediatric house staff and faculty.Data were obtained through an anonymous mail survey. Univariate analyses assessed associations between work-family issues (work-related factors that affect work-family balance, perceived support, work-family--related stress, and proposed solutions) and the following variables: gender, parental status, working status of spouse, and academic rank. Multiple linear regression examined independent predictors of perceived stress.Fifty percent of the 327 respondents cared for dependent children, and 20% expected to care for an elderly person in the next 5 years. Only 5% strongly agreed that their division or department was concerned about supporting members' work-family balance, and 4% strongly agreed that existing programs supported their needs. Eighty-three percent reported feeling stressed as a result of efforts to balance work and family. Independent predictors of stress included perceived need to choose between career and family, increasing age, dependent children, less support from colleagues and supervisors, and female gender.Work-family balance issues are responsible for substantial perceived stress. Academic departments should consider a commitment to supporting faculty who are struggling with these issues, including creation of work-family policies and programs, development of mentoring systems, and reexamination of existing expectations for work practices.

Abstract

Virologic and immunologic responses were examined for 33 human immunodeficiency virus (HIV)-infected children who participated for > or = 96 weeks in a phase 1/2 protocol of 16 weeks of indinavir monotherapy, followed by the addition of zidovudine and lamivudine. At week 96, a median increase of 199 CD4+ T cells/microL and a median decrease of 0.74 log(10) HIV RNA copies/mL were observed. The relationship between control of viral replication and CD4) T cell count was examined. Patients were categorized into 3 response groups on the basis of duration and extent of control of viral replication. Of 21 children with a transient decrease in virus load of > or = 0.7 log(10) HIV RNA copies/mL from baseline, 7 experienced sustained increases in CD4+, CD4+ CD45RA+, and CD4+ CD45RO+ T cell counts. CD4+ CD45RA+ (naive) T cells were the major contributor to CD4+ T cell expansion. Continued long-term immunologic benefit may be experienced by a subset of children, despite only transient virologic suppression.

Abstract

Little is known about the epidemiology and clinical features of esophageal candidiasis (EC) in pediatric AIDS. We therefore investigated the clinical presentation and risk factors of EC in a large prospectively monitored population of HIV-infected children at the National Cancer Institute.We reviewed the records of all HIV-infected children (N = 448) followed between 1987 and 1995 for a history of esophageal candidiasis to characterize the epidemiology, clinical features, therapeutic interventions and outcome of esophageal candidiasis. To understand further the risk factors for EC in pediatric AIDS, we then performed a matched case-control analysis of 25 patients for whom control cases were available.There were 51 episodes of EC documented in 36 patients with 23 male and 13 female patients (0.2 to 17 years; median CD4, count 11/microl), representing a frequency of EC of 8.0%. Concurrent oropharyngeal candidiasis (OPC) was the most common clinical presentation of EC (94%); other signs and symptoms included odynophagia (80%), retrosternal pain (57%), fever (29%), nausea/vomiting (24%), drooling (12%), dehydration (12%), hoarseness (6%) and upper gastrointestinal bleeding (6%). The causative organism documented in 36 episodes (18 from OPC, 17 from endoscopic biopsy and 1 from autopsy) was Candida albicans in all cases. Patients received treatment for EC with amphotericin B (63%), fluconazole (29%), ketoconazole (4%) or itraconazole (1%). A clinical response was documented in all 45 evaluable episodes. In 6 other cases, EC was a final event without contributing to the cause of death. By a conditional logistic regression model for matched data, the best predictor of EC was the presence of prior OPC (P<0.0001), followed by CD4 count and CD4 percentage (P = 0.0002) and use of antibacterial antibiotics (P = 0.0013). The risks associated with low CD4 count were independent of that of prior OPC.EC in pediatric AIDS is a debilitating infection, which develops in the setting of prior OPC, low CD4 counts and previous antibiotics.

Abstract

The safety and preliminary activity of human immunodeficiency virus type 1 (HIV-1) immunogen were evaluated in 10 HIV-1-infected children with disease stage N1,2 or A1,2. Multiple inoculations of 2. 5 or 10 units (U) of HIV-1 immunogen were safe and well tolerated without an acceleration of disease progression. When antiretroviral agents were coadministered, the 10 U dose appeared to be associated with more sustained reduction in plasma HIV-1 RNA than the 2.5 U dose (median log10 HIV-1 RNA at month 18, 3.07 vs. 4.01 copies/mL in 10 U [n=4] vs. 2.5 U [n=3], respectively; P=.034). Levels of regulated-on-activation, normal T cell-expressed and -secreted chemokine produced from HIV-1 immunogen-stimulated lymphocytes in vitro were increased in the children who had HIV-1 immunogen-specific antibody responses (P

Abstract

Among patients with fever and neutropenia during chemotherapy for cancer who have a low risk of complications, oral administration of empirical broad-spectrum antibiotics may be an acceptable alternative to intravenous treatment.We conducted a randomized, double-blind, placebo-controlled study of patients (age, 5 to 74 years) who had fever and neutropenia during chemotherapy for cancer. Neutropenia was expected to be present for no more than 10 days in these patients, and they had to have no other underlying conditions. Patients were assigned to receive either oral ciprofloxacin plus amoxicillin-clavulanate or intravenous ceftazidime. They were hospitalized until fever and neutropenia resolved.A total of 116 episodes were included in each group (84 patients in the oral-therapy group and 79 patients in the intravenous-therapy group). The mean neutrophil counts at admission were 81 per cubic millimeter and 84 per cubic millimeter, respectively; the mean duration of neutropenia was 3.4 and 3.8 days, respectively. Treatment was successful without the need for modifications in 71 percent of episodes in the oral-therapy group and 67 percent of episodes in the intravenous-therapy group (difference between groups, 3 percent; 95 percent confidence interval, -8 percent to 15 percent; P=0.48). Treatment was considered to have failed because of the need for modifications in the regimen in 13 percent and 32 percent of episodes, respectively (P<0.001) and because of the patient's inability to tolerate the regimen in 16 percent and 1 percent of episodes, respectively (P<0.001). There were no deaths. The incidence of intolerance of the oral antibiotics was 16 percent, as compared with 8 percent for placebo (P=0.07).In hospitalized low-risk patients who have fever and neutropenia during cancer chemotherapy, empirical therapy with oral ciprofloxacin and amoxicillin-clavulanate is safe and effective.

Abstract

In order to study the interactions between Candida species and uroepithelial tissue, a tissue explant assay was developed using bladder mucosa harvested from New Zealand white rabbits. Blastoconidia of Candida albicans, Candida tropicalis and Candida glabrata attached to the uroepithelial tissue in similar quantities. However, there was significantly more adherence to the uroepithelium by pre-germinated C. albicans compared with C. albicans blastoconidia. Furthermore, the amount of uroepithelial tissue injury was directly related to the length of exposure of the tissue to Candida. Thus, this tissue explant assay may provide a useful method for investigating properties related to fungal adherence to transitional uroepithelium and organism-mediated tissue injury.

Abstract

To evaluate lymphocyte reconstitution after protease inhibitor therapy in children with human immunodeficiency virus (HIV) infection.Forty-four HIV-infected children receiving ritonavir monotherapy followed by the addition of zidovudine and didanosine were evaluated during a phase I/II clinical trial. The cohort had a median age of 6.8 years and advanced disease (57% Centers for Disease Control and Prevention stage C, 73% immune stage 3) and was naive to protease inhibitor therapy.After 4 weeks of therapy, there was a significant increase in CD4(+) and CD8(+) T cells. CD4(+) T cells continued to increase, whereas CD8(+) T cells returned to baseline by 24 weeks. Unexpectedly, there was a significant increase in B cells. Changes in CD4(+) T-cell subsets revealed an initial increase in CD4(+) CD45RO T cells followed by a sustained increase in CD4(+) CD45RA T cells. Children <6 years of age had the highest increase in all lymphocyte populations. Significant improvement in CD4(+) T-cell counts was observed even in those children whose viral burden returned to pre-therapy levels.Early increases in lymphocytes after ritonavir therapy are a result of recirculation, as shown by increases in B cells and CD4(+) CD45RO and CD8(+) T cells. Children exhibited a high potential to reconstitute CD4(+) CD45RA T cells even with advanced disease and incomplete viral suppression.

Abstract

To assess whether treatment of HIV-positive children by antiretroviral drugs for a 6-month period would improve immune function significantly.Immunological assessment of 89 HIV-positive children who received protease inhibitor monotherapy for 12-16 weeks as part of phase I/II studies, followed by triple antiretroviral therapy for an additional 12 weeks, was conducted. Immunological parameters were assessed in vitro at four time points (at enrollment, at weeks 2-4, at weeks 12-16, and at weeks 24-28). Assessments included: cytokine production by monocytes, T-cell proliferation to mitogen or recall antigens (including an HIV antigen) and apoptotic cell death. Plasma levels of tumor necrosis factor (TNF)-alpha and soluble TNF receptor (sTNF-R) were also measured, in addition to CD4+ T-lymphocyte counts and viral load. In addition, limited analyses were performed on samples from 17 children after 120 weeks of therapy, including 104 weeks of triple therapy.At enrollment, the 89 children exhibited severe immune defects. Antiretroviral therapy raised CD4+ T-lymphocyte counts significantly and decreased viral loads. In contrast, the in vitro immune parameters studied were not improved, except for plasma levels of sTNF-RII which decreased in parallel with the decrease in viral load. In addition, there was a trend towards increased skin test reactivity for the ritonavir-treated children. No differences were seen in the immune parameters whether the patients were treated with mono- or triple therapy. Results obtained after 120 weeks of therapy demonstrated that defective interleukin-12 production was not restored by long-term therapy.After 6 months of therapy, with the exception of decreased sTNF-RII levels, and a trend towards increased skin test reactivity, restoration of several defective cellular immune responses did not occur despite significantly decreased viral loads and increased CD4+ T-lymphocyte counts.

Abstract

We studied the pharmacokinetics of intravenously and orally administered lamivudine at six dose levels ranging from 0.5 to 10 mg/kg of body weight in 52 children with human immunodeficiency virus infection. A two-compartment model with first-order elimination from the central compartment was simultaneously fitted to the serum drug concentration-time data obtained after intravenous and oral administration. The maximal concentration at the end of the 1-h intravenous infusion and the area under the concentration-time curve after oral and intravenous administration increased proportionally with the dose. The mean clearance of lamivudine (+/- standard deviation) in the children was 0.53 +/- 0.19 liter/kg/h (229 +/- 77 ml/min/m2 of body surface area), and the mean half-lives at the distribution and elimination phases were 0.23 +/- 0.18 and 2.2 +/- 2.1 h, respectively. Clearance was age dependent when normalized to body weight but age independent when normalized to body surface area. Lamivudine was rapidly absorbed after oral administration, and 66% +/- 25% of the oral dose was absorbed. Serum lamivudine concentrations were maintained above 1 microM for >/=8 h of 24 h on the twice daily oral dosing schedule with doses of >/=2 mg/kg. The cerebrospinal fluid drug concentration measured 2 to 4 h after the dose was 12% (range, 0 to 46%) of the simultaneously measured serum drug concentration. A limited-sampling strategy was developed to estimate the area under the concentration-time curve for concentrations in serum at 2 and 6 h.

Abstract

To predict long-term (12 weeks or longer) virological responses to antiretroviral treatment from measurements made during the first few days on therapy.Forty-one HIV-1-infected children were treated with ritonavir for 12 weeks followed by triple drug combination treatment, and the kinetics of virus decay in plasma, ritonavir concentration and CD4 cell counts were measured. A robust multivariate pattern recognition method was used for prediction of the longterm virological responses.The virus decay rate constants calculated from measurements of plasma viral RNA concentrations on the first, second, third, fourth and seventh day on therapy, the drug concentrations in the plasma on day seven, and the pretreatment levels of viral RNA and CD4 cell counts, correlated with long-term levels of plasma HIV-1 RNA. The combination of these parameters contained sufficient information for correct and robust prediction of the long-term response in 88% of the treated children. The predictions of individual responses were stable as demonstrated by a cross-validation analysis, which was highly statistically significant (r=0.87) and specific.These results demonstrate that multiple parameters determine the response to antiretroviral therapy and offer a very early measure of individual long-term responses, suggesting that treatment could be optimized after few days of therapy.

Abstract

KNI-272 is a human immunodeficiency virus (HIV) protease inhibitor with potent activity in vitro. We studied the pharmacokinetics of KNI-272 in the plasma and cerebrospinal fluid (CSF) of a nonhuman primate model and after intravenous and oral administration to children with HIV infection. Plasma and CSF were sampled over 24 h after the administration of an intravenous dose of 50 mg of KNI-272 per kg of body weight (approximately 1,000 mg/m2) to three nonhuman primates. The pharmacokinetics of KNI-272 were also studied in 18 children (9 males and 9 females; median age, 9.4 years) enrolled in a phase I trial of four dose levels of KNI-272 (100, 200, 330, and 500 mg/m2 per dose given four times daily). The plasma concentration-time profile of KNI-272 in the nonhuman primate model was characterized by considerable interanimal variability and rapid elimination (clearance, 2.5 liters/h/kg; terminal half-life, 0.54 h). The level of drug exposure achieved in CSF, as measured by the area under the KNI-272 concentration-time curve, was only 1% of that achieved in plasma. The pharmacokinetics of KNI-272 in children were characterized by rapid elimination (clearance, 276 ml/min/m2; terminal half-life, 0.44 h), limited (12%) and apparently saturable bioavailability, and limited distribution (volume of distribution at steady state, 0.11 liter/kg). The concentrations in plasma were maintained above a concentration that is active in vitro for less than half of the 6-h dosing interval. There was no significant increase in CD4 cell counts or decrease in p24 antigen or HIV RNA levels. The pharmacokinetic profile of KNI-272 may limit the drug's efficacy in vivo. It appears that KNI-272 will play a limited role in the treatment of HIV-infected children.

Abstract

Indinavir, an inhibitor of the human immunodeficiency virus type 1 (HIV-1) protease, is approved for the treatment of HIV infection in adults when antiretroviral therapy is indicated. We evaluated the safety and pharmacokinetic profile of the indinavir free-base liquid suspension and the sulfate salt dry-filled capsules in HIV-infected children, and studied its preliminary antiviral and clinical activity in this patient population. In addition, we evaluated the pharmacokinetic profile of a jet-milled suspension after a single dose.Previously untreated children or patients with progressive HIV disease despite antiretroviral therapy or with treatment-associated toxicity were eligible for this phase I/II study. Three dose levels (250 mg/m2, 350 mg/m2, and 500 mg/m2 per dose given orally every 8 h) were evaluated in 2 age groups (<12 years and >/=12 years). Indinavir was initially administered as monotherapy and then in combination with zidovudine and lamivudine after 16 weeks.Fifty-four HIV-infected children (ages 3.1 to 18.9 years) were enrolled. The indinavir free-base suspension was less bioavailable than the dry-filled capsule formulation, and therapy was changed to capsules in all children. Hematuria was the most common side effect, occurring in 7 (13%) children, and associated with nephrolithiasis in 1 patient. The combination of indinavir, lamivudine, and zidovudine was well tolerated. The median CD4 cell count increased after 2 weeks of indinavir monotherapy by 64 cells/mm3, and this was sustained at all dose levels. Plasma ribonucleic acid levels decreased rapidly in a dose-dependent way, but increased toward baseline after a few weeks of indinavir monotherapy.Indinavir dry-filled capsules are relatively well tolerated by children with HIV infection, although hematuria occurs at higher doses. Future studies need to evaluate the efficacy of indinavir when combined de novo with zidovudine and lamivudine.

Abstract

Recent research advances have afforded substantially improved understanding of the biology of HIV infection and the pathogenesis of AIDS. With the advent of sensitive tools for monitoring HIV replication in infected persons, the risk for disease progression and death can be assessed accurately and the efficacy of anti-HIV therapies can be determined directly. Furthermore, when used appropriately, combinations of newly available, potent antiviral therapies can effect prolonged suppression of detectable levels of HIV replication and circumvent the inherent tendency of HIV to generate drug-resistant viral variants. However, as antiretroviral therapy for HIV infection has become increasingly effective, it has also become increasingly complex. Familiarity with recent research advances is needed to ensure that newly available therapies are used in ways that most effectively improve the health and prolong the lives of HIV-infected persons. To enable practitioners and HIV-infected persons to best use rapidly accumulating new information about HIV disease pathogenesis and treatment, the Office of AIDS Research of the National Institutes of Health (NIH) sponsored the NIH Panel To Define Principles of Therapy of HIV Infection. This Panel was asked to define essential scientific principles that should be used to guide the most effective use of antiretroviral therapies and viral load testing in clinical practice. On the basis of detailed consideration of the most current data, the Panel delineated 11 principles that address issues of fundamental importance for the treatment of HIV infection. These principles provide the scientific basis for the specific treatment recommendations made by the Panel on Clinical Practices for the Treatment of HIV Infection sponsored by the Department of Health and Human Services and the Henry J. Kaiser Family Foundation. The reports of both of these panels are provided in this supplement. Together, they summarize new data and provide both the scientific basis and specific guidelines for the treatment of HIV-infected persons. This information will be of interest to health care providers, HIV-infected persons, HIV and AIDS educators, public health educators, public health authorities, and all organizations that fund medical care of HIV-infected persons.

Abstract

Ritonavir, a potent antiretroviral protease inhibitor, has been approved for the treatment of adults and children with human immunodeficiency virus (HIV) infection. In a phase I/II study, we assessed the safety, tolerability, and pharmacokinetic profile of the oral solution of ritonavir in HIV-infected children and studied the preliminary antiviral and clinical effects.HIV-infected children between 6 months and 18 years of age were eligible. Four dose levels of ritonavir oral solution (250, 300, 350, and 400 mg/m given every 12 hours) were evaluated in two age groups (=2 years, >2 years). Ritonavir was administered alone for the first 12 weeks and then in combination with zidovudine and/or didanosine. Clinical and laboratory parameters were monitored every 2 to 4 weeks.A total of 48 children (median age, 7.7 years; range, 0.5 to 14.4 years) were included in this analysis. Dose-related nausea, diarrhea, and abdominal pain were the most common toxicities and resulted in discontinuation of ritonavir in 7 children. Ritonavir was well absorbed at all dose levels, and plasma concentrations reached a peak 2 to 4 hours after a dose. CD4 cells counts increased by a median of 79 cells/mm3 after 4 weeks of monotherapy and were maintained throughout the study. Plasma HIV RNA decreased by 1 to 2 log10 copies/mL within 4 to 8 weeks of ritonavir monotherapy, and this level was sustained in patients enrolled at the highest dose level of 400 mg/m for the 24-week period.The oral solution of ritonavir has potent antiretroviral activity as a single agent and is relatively well tolerated by children when administered alone or in combination with zidovudine or didanosine.

Abstract

Pathogenesis of invasive candidiasis may involve regulatory activities of Th2 immunity on phagocytic host defenses. The effects of interleukin (IL)-4 on antifungal capacity of human mononuclear phagocytes against Candida albicans were studied. Incubation of adherent mononuclear leukocytes from healthy donors with IL-4 (1-5 ng ml(-1)) at 37 degrees C for 2-4 days suppressed uptake of C. albicans blastoconidia in the presence of human serum (P < or = 0.01), and anti-IL-4 inhibited its suppressive effect. The effect of IL-4 was protein synthesis-dependent. Interferon-gamma (0.25-25 ng ml(-1)), granulocyte-macrophage colony-stimulating factor (CSF, 20 ng ml(-1)), macrophage-CSF (15 ng ml(-1)) but not IL-10 (100 ng ml(-1)) somewhat counteracted the suppressive effect of IL-4. In contrast, mannose receptor-mediated uptake of blastoconidia in the absence of serum was increased by IL-4. Killing of conidia was decreased after incubation of morphonuclear leukocytes with IL-4 for 2 days (P < 0.05). While superoxide anion production in response to phorbol myristate acetate was decreased by IL-4 (P < 0.05), it was not altered in response to blastoconidia and pseudohyphae. Morphonuclear leukocyte-induced pseudohyphal damage also remained unaltered. These findings suggest that IL-4 plays its detrimental role in invasive candidiasis by predominantly suppressing uptake and killing of blastoconidia by morphonuclear leukocytes. Anti-IL-4, IFN-gamma, GM-CSF and M-CSF appear to counteract suppression of morphonuclear leukocyte phagocytic activity suggesting new approaches to the management of disseminated candidiasis.

Abstract

The safety, tolerance, and pharmacokinetics of amphotericin B lipid complex (ABLC) were studied in a cohort of pediatric cancer patients. Six children with hepatosplenic candidiasis (HSC) received 2.5 mg of ABLC/kg of body weight/day for 6 weeks for a total dosage of 105 mg/kg. Mean serum creatinine (0.85 +/- 0.12 mg/dl at baseline) was stable at the end of therapy at 0.85 +/- 0.18 mg/dl and at 1-month follow-up at 0.72 +/- 0.12 mg/dl. There was no increase in hepatic transaminases. Mean plasma concentrations over the dosing interval (C(ave)) and area under the curve from 0 to 24 h (AUC(0-24h)) increased between the first and seventh doses but were similar between doses 7 and 42, suggesting that steady state was achieved by day 7 of therapy. Following the final (42nd) dose of ABLC, mean AUC(0-24h) was 11.9 +/- 2.6 microg h/ml, C(ave) was 0.50 +/- 0.11 microg/ml, maximum concentration of the drug in whole blood was 1.69 +/- 0.75 microg/ml, and clearance was 3.64 +/- 0.78 ml/min/kg. Response of hepatic and splenic lesions was monitored by serial computerized tomographic and magnetic resonance imaging scans. The five evaluable patients responded to ABLC with complete or partial resolution of physical findings and of lesions of HSC. During the course of ABLC infusions and follow-up, there was no progression of HSC, breakthrough fungemia, or posttherapy recurrence. Hepatic lesions continued to resolve after the completion of administration of ABLC. Thus, ABLC administered in multiple doses to children was safe, was characterized by a steady state attainable within 1 week of therapy, and was effective in treatment of HSC.

Abstract

This is the first in a series of practice guidelines commissioned by the Infectious Diseases Society of America through its Practice Guidelines Committee. The purpose of these guidelines is to provide assistance to clinicians when making decisions on treating the conditions specified in each guideline. The targeted providers are internists, pediatricians, and family practitioners. The targeted patients and setting for the fever and neutropenia guideline are hospitalized individuals with neutropenia secondary to cancer chemotherapy. Panel members represented experts in adult and pediatric infectious diseases and oncology. The guidelines are evidence-based. A standard ranking system was used for the strength of the recommendations and the quality of the evidence cited in the literature reviewed. The document has been subjected to external review by peer reviewers as well as by the Practice Guidelines Committee and was approved by the IDSA Council. An executive summary, algorithms, and tables highlight the major recommendations. The guideline will be listed on the IDSA home page at http://www.idsociety.org.

Abstract

Children with human immunodeficiency virus (HIV) infection have an increased susceptibility to severe and unusual infections, malignancies, and disorders characterized by abnormal lymphoproliferation (e.g., lymphoid interstitial pneumonitis). We report a novel disease entity associated with pediatric HIV infection that is characterized by massive enlargement of the thymus as a result of lymphoid hyperplasia and multicystic changes.Eight patients with HIV infection and cystic enlargement of the thymus are subject of this report. The status of their HIV disease and its clinical and radiologic manifestations at the time of diagnosis of the mediastinal mass are described. Tissue specimens were obtained from six patients and examined by microscopy and immunohistochemistry. The specimens were also evaluated for the evidence of HIV and Epstein-Barr virus by in situ hybridization.Patients were between 2.1 and 12.1 years of age, with CD4+ cell counts between 102 and 733 cells/mm3. In all eight cases an anterior mediastinal mass was discovered incidentally on radiography of the chest, and computed tomography of the chest revealed a multicystic appearance. Histologic examination demonstrated distortion of the thymic architecture by focal cystic changes, lymphoid follicular hyperplasia, diffuse plasmacytosis, and multinucleated giant cells. In situ hybridization revealed HIV particles on the surface of follicular dendritic cells. Further, results of in situ hybridization for EBV were positive in lymphoid cells from biopsy samples of four patients. The patients were followed between 8 months and 4.8 years. In five patients the mass either decreased in size or resolved completely.We describe a series of children with HIV infection and multilocular thymic cysts. We hypothesize that aberrant immunoregulation in these HIV-infected children leads to follicular hyperplasia and multicystic changes in the thymus, causing massive enlargement. EBV infection might also contribute to the pathogenesis of this process. Because none of our patients had symptoms from the mass, and there was no evidence of malignancy in the examined biopsy samples, it seems prudent to manage such children with careful follow-up examinations.

Progression of human immunodeficiency virus infection in children is related to the interaction of the virus, the immune system, and then some.Clinical infectious diseases Pizzo, P. A.1997; 24 (5): 975-976

Abstract

To determine retrospectively the prevalence of positive cytomegalovirus (CMV) cultures in pediatric patients with human immunodeficiency virus infection.We reviewed the records of 273 children with human immunodeficiency virus infection referred to the Pediatric Branch of the National Cancer Institute for whom CMV cultures were performed between January, 1991, and October, 1994.Of this group 189 patients (69%) had negative CMV cultures and 84 (31%) had positive cultures. The prevalence of CMV-related disease was 9% for the entire group, including 4 (2.1%) patients with negative CMV cultures. Among the 84 patients with positive CMV cultures, 21 (25%) had evidence of CMV disease. Patients with positive CMV cultures had a statistically significant decrease in survival in the presence of severe immunocompromise defined as an age-corrected CD4 count of < 21%. Nine of 35 (26%) autopsies performed demonstrated evidence of CMV disease, including 7 patients with disseminated CMV disease.Although CMV disease appears to be less frequent in children than adults, CMV infection still contributes significantly to morbidity and mortality in this population, especially when combined with severe immunosuppression.

Abstract

Aspergillosis is an uncommon yet serious opportunistic infection in patients with AIDS. It has been extensively reported in HIV-infected adult patients. To our knowledge there are no studies that describe the epidemiology, clinical manifestations and outcome of aspergillosis in a large HIV-infected pediatric population.We reviewed the records of all 473 HIV-infected children followed in the Pediatric Branch of the National Cancer Institute for 9 years from 1987 through 1995 for the presence of Aspergillus infection.Seven (1.5%) patients developed invasive aspergillosis during the study period. All patients had low CD4 counts reflecting severe immunosuppression. Sustained neutropenia (> 7 days) or corticosteroid therapy as a predisposing factor for invasive aspergillosis was encountered in only two patients (28%). Invasive pulmonary aspergillosis developed in five patients and cutaneous aspergillosis in two. The most common presenting features in patients with pulmonary aspergillosis were fever, cough and dyspnea. Patients with cutaneous aspergillosis were diagnosed during life and successfully treated with amphotericin B and surgery, whereas diagnosis of pulmonary aspergillosis was made clinically in only one patient.Aspergillosis is an uncommon but highly lethal opportunistic infection in HIV-infected children. Invasive pulmonary aspergillosis should be considered in the differential diagnosis in febrile, HIV-infected children with persistent pulmonary infiltrates.

Abstract

The success of managing the infectious complications of acute leukemia has permitted oncologists to develop new approaches to induction and high-dose therapy. The single most important risk factor for infection is the duration of absolute neutropenia. Historically, most attention was directed towards gram negative aerobes, especially Pseudomonas aeruginosa, but in recent years gram positive bacteria, generally considered to be less virulent, have become the most frequent isolates in most centers. A recent disturbing trend is the isolation of vancomycin-resistant enterococci. A recent controversy has been whether to use empirical vancomycin; the Centers for Disease Control has issued a formal recommendation discouraging empirical vancomycin in the febrile neutropenic patient. Empirical monotherapy has replaced combination therapy in many institutions except where there has been an increase in resistant isolates. In patients who remain profoundly neutropenic, fungal infections represent a serious source of secondary infection, especially species of Candida and Aspergillus. Recently lipid-based formulations of amphotericin B have offered reduced nephrotoxicity. Less toxic antifungals, the azoles, which include fluconazole and itraconazole, offer an attractive alternative to amphotericin B. New patterns of invasive mycoses have emerged, as for example hepatosplenic candidiasis, presenting new problems in diagnosis and therapy. The successful management of virus infections with herpes simplex, cytomegalovirus, varicella zoster, and Epstein Barr virus is based on early recognition and careful attention to prevention.

Abstract

Empiric antibiotic therapy has become a standard of care for the febrile neutropenic patient. Many clinical trials over the previous three decades have demonstrated that a variety of antibiotic combinations and more recently potent antibiotic monotherapies may preserve the patient through the critical time of fever and neutropenia. Recently attempts have been made to identify "low risk" patients who may not require traditional, intensive, hospitalized intravenous antimicrobial therapy. Therefore the need for new treatment alternatives for the febrile neutropenic pediatric cancer patient in particular revolves around the desire for less complex regimens, agents with minimal toxicity and expense and the option of an oral formulation for outpatient management.Fluoroquinolones, especially ciprofloxacin and ofloxacin, are examined in this paper as potential oral alternatives for managing the low risk neutropenic pediatric cancer patient population. Attention must be paid to their antibacterial spectra, however, and in some cases fluoroquinolones should be combined with a second agent for additional Gram-positive coverage.Several studies, including one ongoing trial at the National Cancer Institute, have shown the potential benefits of oral fluoroquinolone therapy among low risk febrile neutropenic patients. Joint complaints in children after ciprofloxacin therapy in the National Cancer Institute trial thus far have been minimal, reversible and felt to be unrelated to ciprofloxacin treatment.The use of outpatient therapy, such as the fluoroquinolones, to manage febrile neutropenic episodes must be approached with caution and should be undertaken only in selected low risk patients.

Abstract

Invasive aspergillosis has emerged as a frequent and serious infection in immunocompromised patients. We studied the effects of human IL-10 on antifungal activity of monocytes (MNCs) from healthy adults against Aspergillus fumigatus after incubation with IL-10 at 37 degrees C for 2 to 4 days. IL-10 (2-20 ng/ml)-pretreated MNCs exhibited approximately 40% suppression of superoxide anion (02-) production in response to PMA and FMLP (p < or = 0.003), and anti-IL-10 containing supernatant neutralized the IL-10 effect. IL-10 (20 ng/ml)-pretreated MNCs exhibited decreased damage of Aspergillus hyphae after 2 to 4 days (55-98% decrease, p < or = 0.04). The MNC phagocytic activity against conidia, as assessed by microscopy (percentage of phagocytosing MNCs and number of intracellular conidia per MNC) as well as by colony counting (colonies grown from intracellular conidia), was enhanced by 127% (p = 0.006), 14% (p = 0.03), and 23% (p = 0.009), respectively. MNC capacity to inhibit intracellular germination was marginally enhanced (p = 0.04) and intracellular conidiocidal activity was unaffected by IL-10. IL-4 (5 ng/ml) did not change the up-regulatory IL-10 effect on phagocytosis. IFN-gamma (25 ng/ml) and granulocyte-macrophage CSF (20 ng/ml), but not macrophage CSF (15 ng/ml), appeared to counteract suppressive IL-10 effects. Thus, IL-10 suppresses oxidative burst and antifungal activity of MNCs against Aspergillus hyphae, while increasing their phagocytic activity. These findings further elucidate a potential role of IL-10 in the pathogenesis of invasive aspergillosis, which may lead to new treatment strategies.

Abstract

Fever in the neutropenic patient following myelosuppressive chemotherapy is a medical emergency. Appropriate antimicrobial therapy can dramatically reduce infection-related morbidity and mortality. This article reviews the rationale and methodology of treatment as well as its applicability to other neutropenic states. The utility of adjunct therapy with granulocyte- stimulating compounds is also discussed.

Abstract

The amount of human immunodeficiency virus (HIV) type 1 RNA and the presence of a codon 215 mutation indicative of zidovudine resistance were evaluated in cerebrospinal fluid (CSF) and plasma obtained from HIV-1-infected children. The level of HIV-1 RNA in CSF was highest in children with severe encephalopathy (n = 25; median, 430 copies/mL; range, 0-2.2 x 10(5) copies/mL) followed by the moderately encephalopathic (n = 7; median, 330; range, 0-1130) and nonencephalopathic groups (n = 9; median, 0; range, 0-566) (P = .007). There was no correlation between CSF and plasma HIV-1 RNA levels. Five of 7 children with the codon 215 mutation in CSF had a progression of encephalopathy, while all 8 children with wild type codon 215 had improved or stable disease during zidovudine treatment (P = .007). These findings suggest that increased viral replication and emergence of drug-resistant HIV-1 variants within the central nervous system may play a role in progression of HIV encephalopathy.

Abstract

Recent studies have used potent antiviral agents to investigate the kinetics of HIV infection in vivo. They provided estimates for important kinetic parameters, including the decay constants for circulating virus and infected CD4+cells. However, since all of these studies fundamentally rely on the use of antiviral agents, it would be useful to develop other approaches capable of independently verifying the values of the kinetic parameters through other means. Since CD4+ cells are known to exhibit diurnal variations and since there have been suggestions that circulating virus concentrations also vary in a diurnal fashion, as well as nonperiodically, we developed a mathematical model to describe those natural variations. The model predicted variations in viral RNA concentrations and produced estimates of the values of viral kinetic parameters without the use of antiviral agents. To compare the model with experimental data we measured the temporal dependence of the concentration of plasma viral RNA obtained from pediatric HIV-1 patients. The data analysis led to finding diurnal variation in the viral RNA and an estimate of the circulating virus half-life in the order of few hours, in reasonable agreement with the estimates obtained using antiviral agents. These results are the first demonstration of diurnal variations in AIDS patients and confirm the order of magnitude of the virus half-life found by using antiviral drugs. These findings may have implications for understanding HIV-1 pathogenesis and the development of therapeutic protocols.

Abstract

Disclosure of the diagnosis of human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS) to a child is a controversial and emotionally laden issue. To understand the factors that affect the process of disclosure and its consequences, we studied 99 parent-child dyads recruited from patients being treated at the National Cancer Institute (NCI). Parents and HIV-infected children were interviewed and administered several standardized measures. Parental depression, family environment, social support satisfaction, socioeconomic status, child and parent gender, child's age, parental HIV serostatus, and disease severity were used to predict disclosure status. Results indicate that the majority of caregivers do disclose the diagnosis to the child, usually with no ill effects, and that age is the most significant predictor of whether or not a child has been told. The Centers for Disease Control and Prevention currently estimate that there are over 6611 children with AIDS (under age 13), and 2184 adolescents with AIDS (ages 13-19) in America. As an increasing number of children who are born infected with HIV live to older ages, the question of when and how to talk with them about their illness becomes more crucial. In addition to the growing number of children infected with HIV, there are many thousands of children profoundly affected by the impact of this disease on a close family member--a mother, father, sibling, or other relative in the kinship network. Yet, the initial reaction most adults have upon learning of their own, or of a family member's, HIV diagnosis is that the diagnosis must be kept a closely guarded secret. One reason frequently cited by parents and family members is their fear that the stigma of AIDS will have a negative impact on their children and their families. Disclosure of an HIV diagnosis to a child is a controversial and emotionally laden issue in the pediatric health-care community as well. However, no systematic research has studied the issues that surround disclosure of an HIV diagnosis to the patient and the factors that predict disclosure.

Abstract

To evaluate the radiologic and follow-up features of multilocular thymic cysts in children with human immunodeficiency virus (HIV) infection.Four HIV-infected children with large anterior mediastinal masses depicted at routine chest radiography underwent ultrasonography (US), unenhanced and contrast material-enhanced computed tomography (CT), and unenhanced and gadolinium-enhanced MR imaging of the chest. Gallium scanning was also performed in three of the four children. The patients underwent follow-up radiologic examinations for 8-15 months.The multiloculated nature of the masses was depicted at contrast-enhanced but not unenhanced CT. Similarly, the septations were depicted on T2-weighted, short inversion time inversion-recovery (STIR), and contrast-enhanced T1-weighted, MR images but not on the unenhanced T1-weighted images. US scans depicted the septations within each mass, but findings were technically limited because only portions of each mass were depicted. Gallium scans in three masses depicted uptake of radionuclide in two and no uptake in one. Surgical biopsy was performed in each mass: Follicular hyperplasia and diffuse plasmacytosis of the thymus were found but not evidence of neoplastic or infectious origin. At follow-up, the mass decreased in volume in two patients, did not change in one patient, and increased in volume in one patient.HIV-infected patients with asymptomatic mediastinal masses depicted at routine chest radiography should undergo contrast-enhanced CT. If a solid mass is depicted, biopsy should be performed to exclude neoplastic or infectious origins. If a multiloculated anterior mediastinal mass is depicted, symptomatic follow-up is adequate since the finding represents a rare multilocular thymic cyst that does not have negative clinical implications.

Abstract

Central nervous system (CNS) abnormalities are significant and frequent complications of human immunodeficiency virus (HIV-1) infection in infants and children. Although the predominant cause of neurological and neuropsychological abnormalities appears to be related to HIV infection of the CNS, other factors including malnutrition may also play a role. We retrospectively evaluated the association of change in body weight with changes in neurocognitive function, ventricular brain ratio, and cerebrospinal quinolinic acid levels in a small cohort of children (n=15; mean age 6.3 years) with symptomatic HIV-1 disease before and after 6 months of antiretroviral therapy with continuous intravenous infusion of zidovudine (ZVD). Significant increases in weight and neurocognitive function as well as decreases in ventricular brain ratio and cerebrospinal quinolinic acid levels were noted after therapy. Only the relation between increase in weight and decrease in ventricular brain ratio was statistically significant (P< .01); contrary to expectations, an increase in weight seemed to correlate with a decrease in neurocognitive function (NS). Another group of children treated at the same time with oral intermittent ZVD, but otherwise receiving the same care did not show the same magnitude of improvement in neurocognitive function. These results seem to suggest that general supportive and medical care as well as nutritional factors may only play a limited role in the neurocognitive improvements after antiretroviral therapy with continuous infusion ZVD. Our sample size was, however, small and the nutritional measure rather global; thus these findings have to be considered as very preliminary.

Abstract

Children with human immunodeficiency virus (HIV) infection have multiple complications associated with the disease process. Many of these complications are potentially painful and could affect the patient's quality of life. We examined the incidence and characteristics of the perception of pain in a cohort of families with children with HIV infection.A questionnaire was developed and validated with a cohort of families with children with cancer. In a survey of families at the Pediatric Branch of the National Cancer Institute, 61 children with HIV infection and their care givers, along with 19 children with cancer and their care givers, were interviewed to determine the incidence and impact of pain.Fifty-nine percent of the HIV-infected children and 55% of their care givers described pain as a component of their illness that impacted on their lives. Younger children and girls tended to report more pain. There was also a tendency for biological parents to expect and to treat more pain than foster parents, although there was no difference in the incidence of pain that biological and foster parents reported for their children. No differences were found between parents who were HIV positive and those who were not. In addition, no correlations were noted in incidence, expectation, or impact of pain with disease progression or surrogate markers such as CD4 counts. Pain in HIV-infected patients tended to be either in the gastrointestinal tract or limbs and usually responded to nonsteroidal anti-inflammatory therapy. The patients with cancer reported an incidence (47%) and impact of pain similar to those of previously reported studies on pediatric patients with cancer.Pain is common among children infected with HIV and can adversely impact on their lives, and its management should be a component of the general care of these patients.

Abstract

Cryptococcosis is a common opportunistic infection in adults with AIDS. Few cases of cryptococcosis complicating pediatric AIDS have been reported. To our knowledge there are no studies that describe the epidemiology, clinical manifestations and outcome of cryptococcosis in a large population of HIV-infected children.We identified the cases of cryptococcosis through a retrospective review of the hospital records of the 473 HIV-infected children prospectively monitored in the Pediatric Branch of the National Cancer Institute during the 8 years from 1987 to 1995.Four (0.85%) patients developed cryptococcosis during the study period. All patients had profound depression of the absolute CD4 counts, a history of previous opportunistic infections, and onset of cryptococcosis in the second decade of life. Cryptococcosis developed as a disseminated infection or a localized process of the lungs. Intermittent fever was the most common presenting manifestation. Serum cryptococcal antigen was positive in all patients and gradually declined after the institution of the antifungal therapy. All patients were treated with amphotericin B with or without flucytosine as initial therapy. Suppressive therapy consisted of fluconazole with or without flucytosine. There were no deaths due to Cryptococcus neoformans.Cryptococcosis is an infrequent yet treatable opportunistic infection of advanced pediatric AIDS that may present with subtle manifestations and warrants careful consideration in the evaluation of febrile HIV-infected children.

Abstract

To define the risk factors related to the occurrence of fungemia in children infected with human immunodeficiency virus (HIV), we performed a matched case-control study. During a 6-year period (1987-1993), fungemia developed in 22 (6.3%) of 347 HIV-infected children observed at the Pediatric Branch of the National Cancer Institute. Each of these 22 cases was matched by age and gender with three controls. Multiple logistic regression indicated that the best predictor of fungemia in this population was the presence of a central venous catheter placed for > 90 days (P < .00001), followed by a group of risk factors composed of 10 independent variables adjusted for a CD4 cell count of < 100/MicroL (P < .045). Those variables included treatment with more than three antibiotics, treatment with more than three parenteral antibiotics, > 30 days of antibiotic treatment, bacterial infections, > 30 days in the hospital, hypoalbuminemia, C3 (Centers for Disease Control and Prevention) classification of HIV infection, and malnourishment. We conclude that prolonged placement of central venous catheters is the most important risk factors for fungemia in HIV-infected children and that the risk of fungemia is further influenced by antibacterial therapy, catheter manipulation, and host response.

Abstract

Lymph nodes serve as reservoirs for the replication of human immunodeficiency virus (HIV) type 1. Comparison of serial measurements of virus burden in lymph nodes and peripheral blood after a change in antiretroviral therapy may provide insights into pathogenic mechanisms and permit a more accurate assessment of a therapeutic response.Nevirapine was added to the drug regiment of eight children with HIV infection treated with the combination of zidovudine and didanosine who had increasing levels of serum p24 antigen. Lymph node biopsies were performed at entry and after 12 weeks of therapy.Neither CD4 counts nor p24 antigen level correlated with the degree of viremia as measured by ribonucleic acid copy numbers in plasma. Correlations were found between HIV DNA copy number in peripheral blood mononuclear cells and HIV DNA copy number in lymph nodes (p = 0.02), as well as between peripheral blood CD4 counts and lymph node architecture. The HIV signals in the lymph nodes conformed to the anatomic organization of apical light zones in the germinal centers; however, in more advanced disease stages, organized germinal centers disappeared as evidence by a decline in the extent of the follicular dendritic network.Lymph node biopsies in this small number of HIV-infected children revealed a progressive loss of an organized architecture, especially of the follicular dendritic network. This correlated with a progressive loss of CD4+ cells but not with other measures of disease stage, including viral load, as measured by ribonucleic acid copy numbers.

Abstract

Hematopoietic abnormalities are common in patients infected with the human immunodeficiency virus (HIV). We evaluated the role of diagnostic bone marrow aspirations and biopsies in HIV-infected children.Seventy-eight bone marrow biopsies and aspirates performed during the last 8 years at the Pediatric Branch of the National Cancer Institute from 60 children with symptomatic HIV infection were reviewed retrospectively. The results were correlated with clinical stage, use of antiretroviral therapy or hematopoietic growth factors, and hematopoietic parameters.Most patients (84%) showed a normal or hypercellular marrow, associated with diffuse lymphocytosis (50%) or therapy with hematopoietic growth factors (33%). Dyspoietic features were very common in all three cell lineages. Twenty-seven (44%) of the patients had decreased iron stores in the bone marrow that correlated with iron deficiency as documented by serum tests in more than one-third of our study population. Bone marrow cultures were not more helpful than peripheral cultures in establishing the diagnosis of an opportunistic infection.Although bone marrow abnormalities are very common in HIV-infected children, they are rarely specific. The role of diagnostic bone marrow aspirates and biopsies appears to be limited, and this invasive procedure should be reserved for specific situations (e.g., to rule out a malignancy).

Abstract

The safety, tolerability, pharmacokinetic profile, and preliminary activity of lamivudine (2'-deoxy-3'-thiacytidine), a novel cytidine nucleoside analogue with antiretroviral activity, in human immunodeficiency virus (HIV)-infected children beyond the neonatal period were studied. Ninety children received dosages of 1-20 mg/kg/day. Pharmacokinetic evaluation demonstrated serum and cerebrospinal fluid concentrations that increased proportionally to dose. As of January 1994, 11 children had been withdrawn from study for disease progression and 10 because of possible lamivudine-related toxicity, and 6 had died. CD4 and CD8 cell counts remained stable over 24 weeks in therapy-naive children and decrease slightly in previously treated children. Quantitative immune complex-dissociated p24 antigen and HIV RNA were decreased significantly at 12 and 24 weeks. In vitro resistance to lamivudine was documented in sequential virus isolates from some patients by 12 weeks. Lamivudine was well-tolerated and exhibited virologic activity in children, although future use in children is likely to be in combination antiretroviral regimens.

Abstract

Rated observations of videotapes were made of 16 variables representing 5 behavioral domains (task orientation, positive social-emotional, motor skills, expressive speech, and activity) on a sample of 83 HIV-infected children. Comparisons were made on the rated behaviors between children classified as either encephalopathic or nonencephalopathic. Analyses were conducted separately for infants (M age = 1.80 years) and older children (M age = 5.15 years). The nonencephalopathic infants exhibited higher activity levels and were superior in motor and verbal skills and showed more social and emotional responsiveness than did the encephalopathic group. The older nonencephalopathic children functioned in a more adaptive and appropriate manner than did the encephalopathic children in all domains of behavior. Independently made Q-sort ratings of behaviors during developmental testing were highly correlated with conceptually congruent ratings of the videotaped behaviors.

Abstract

To investigate the dynamic interplay between human immunodeficiency virus type I (HIV-1) replication and the extent of immune destruction in HIV-1-infected children, virus burden in lymphoid tissues (LN) and peripheral blood was compared with changes in LN architecture and cytokine levels constitutively expressed in LN. In agreement with results of a preliminary study, the plasma HIV-1 RNA level correlated with the amount of provirus in LN. However, the level was also associated with a degree of destruction of lymphoid follicular architecture and an alteration of immune cytokine expression. Expression of interleukin (IL)-4 was higher in LN with higher virus replication. Reduction of plasma viremia was associated with an increase in IL-2 mRNA levels in LN. These findings suggest that measurable virus burden in the peripheral blood is not a simple reflection of viral replication in LN but is also influenced by the extent of progressive immune destruction.

Abstract

Treatment of fever and neutropenia in cancer patients has been recognized for 30 years as a medical emergency, requiring prompt in-hospital evaluation and institution of broad-spectrum intravenous (i.v.) antibiotics. This action was deemed necessary due to the high frequency of life-threatening infections in febrile neutropenic patients, with no way to distinguish patients who are infected from those who are not. In recent years, it has become clear that not all neutropenic cancer patients are at the same level of risk for developing severe infections or life-threatening complications during neutropenia. Those who are at low risk may be candidates for treatment outside the hospital setting, either with i.v. regimens or potent oral antibiotics. The identification of low-risk febrile neutropenic patients and the specific outpatient approaches that have been tested to date are discussed. Outpatient management of fever during neutropenia could obviously be much less costly than standard inpatient care and could improve quality of life for low-risk patients undergoing cancer therapy.

Abstract

To evaluate whether recombinant human granulocyte-macrophage colony-stimulating factor (GM-CSF) reduces the hematologic toxicities and supportive care requirements of an intensive combination chemoradiotherapy regimen in pediatric and young adult sarcoma patients.Thirty-seven newly diagnosed patients age 1 to 25 years were randomized to receive 18 cycles of chemotherapy alone or with GM-CSF beginning in cycle 3. GM-CSF (5 to 15 micrograms/kg/d subcutaneously) was begun 24 hours after the completion of chemotherapy and continued through day 19 of each cycle or until the absolute granulocyte count (AGC) was > or = 500/microliter on 2 consecutive days.GM-CSF reduced the median duration of grade 4 granulocytopenia from 9.0 days (range, 2 to 24) to 7.0 days (range, 1 to 21) (P < .0001), but did not significantly affect the grade of granulocyte nadir. No differences were seen in the incidence or types of infectious complications, incidence or duration of hospitalization and antimicrobial therapy, response to chemotherapy, or event-free or overall survival. GM-CSF was associated with more severe and protracted thrombocytopenia (median platelet nadir, 29,500/microliter [range, 3,000 to 288,000] v 59,000/microliter [range, 3,000 to 309,000], P < .0001; median time to recovery > 75,000/microliter, 16.0 days [range, 0 to 61] v 14.0 days [range, 0 to 38], P < .0001).GM-CSF does not produce clinically meaningful reductions in the degree or duration of severe granulocytopenia following intensive multiagent chemotherapy, but is associated with worsened thrombocytopenia. GM-CSF also does not reduce the need for hospitalization or the incidence of febrile neutropenia and infectious complications. We conclude that the costs and increased toxicities associated with the use of this agent are not justified by its minimal clinical benefit for regimens of this level of intensity.

Abstract

Patients with immunodeficiency disorders, including children infected with HIV type 1, are at increased risk to develop a malignancy. Although the exact incidence is not clear, an excess of non-Hodgkin's lymphomas, soft tissue tumors, and, in the case of adolescent girls, cervical carcinomas, has been reported in HIV-infected children. Kaposi's sarcoma is rare in children as compared with HIV-infected adults. To understand the pathogenesis of these disorders, one must take into account the multiple interactions between the immunodeficient host, the cytokine dysregulations, and the concurrent infection with many, potentially oncogenic, viruses. Treatment is often complicated by multiple HIV-associated organ dysfunctions as well as drug interactions and infectious complications secondary to severe immmunosuppression. Nonetheless, preliminary results with dose-intensive short-duration chemotherapeutic regimens have been encouraging, and HIV-infected children who develop cancer are likely to benefit from antineoplastic therapy and supportive care.

Abstract

Pulmonary complications occur commonly during HIV infection. The aim of this study was to evaluate the clinical value of lung tissue examination in the diagnosis and treatment of pulmonary disorders in children with HIV infection.The medical records of 347 children enrolled between January, 1990, and April, 1994, into various antiretroviral therapy protocols were reviewed to identify patients who underwent a lung biopsy.Fourteen patients underwent diagnostic lung biopsies on 16 separate occasions. The most common radiologic findings were nodular infiltrates which were localized in 7 patients and diffuse in 6. Eight patients presented with fever and progressive respiratory distress unresponsive to empiric therapy, whereas the rest had progressive nodular infiltrates. The pathologic diagnoses included opportunistic infection in 7 patients, lymphocytic interstitial pneumonitis in 5, non-Hodgkin's lymphoma in 3 and interstitial fibrosis in 1. The biopsy led to a major change in the treatment of 7 patients which resulted in a significant improvement of the pulmonary process in all of them. In an additional patient the excisional biopsy proved curative.When patients are selected appropriately, lung biopsy might have a significant impact on therapy and outcome in HIV-infected children with pulmonary infiltrates.

Abstract

The ex vivo effects of macrophage colony-stimulating factor (M-CSF) on antifungal and antibacterial activities of human elutriated monocytes were studied. Cells were isolated prior to the initiation of therapy, on day 3 and at week 7, in six patients with an advanced malignancy receiving M-CSF in a phase I study. Superoxide anion production by monocytes in response to N-formyl methionyl leucyl phenylalanine was enhanced at day 3 of therapy (P = 0.011). In addition, at day 3, fungicidal activity against blastoconidia of Candida albicans was enhanced by M-CSF treatment (P = 0.026), whereas antifungal activity against hyphae of Aspergillus fumigatus was not significantly changed. Bactericidal activity against Staphylococcus aureus was increased at day 3 (P = 0.004). By Northern blot analysis, M-CSF does not upregulate the expression of components of the NADPH-oxidase, the multicomponent enzyme system responsible for generation of superoxide radicals by monocytes. Instead, the predominant effect of M-CSF on circulating monocytes is probably a post-transcriptional effect. In conclusion, these findings suggest that administration of M-CSF to patients may enhance microbicidal activities and thus may provide a useful adjunct to conventional antimicrobial therapy.

Abstract

To study thyroid function in children infected with human immunodeficiency virus (HIV) and determine whether there are correlates of thyroid dysfunction with disease progression.Total and free thyroxine, triiodothyronine, reverse triiodothyronine, thyrotropin, and thyroxine binding globulin (TBG) were measured in 167 children with HIV infection (age, 1 to 19 years; mean, 9.15 years).Pediatric Branch, National Cancer Institute.Free thyroxine was at or below the lower limit of normal (normal, 1.0 to 1.9 ng/dl) in 18% of the children; thyrotropin and TBG levels were above the normal range in 31% and 30%, respectively. There was an inverse correlation between CD4+ cell count and thyrotropin, and between CD4+ cell count and TBG. No correlation was found between thyroid function and other disease symptoms or medications.These findings indicate that thyroid abnormalities occur more frequently in children with HIV infection than was previously reported, have a different profile from the thyroid abnormalities associated with other chronic disease conditions, and correlate with disease progression.

Abstract

Treatment with corticosteroids is an important risk factor for development of invasive aspergillosis. We evaluated the effect of dexamethasone (DEX) on superoxide anion (O2-) release and damage caused by elutriated human monocytes (EHM) on unopsonized hyphae of Aspergillus fumigatus. In addition, we studied the effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma) on these functions of DEX-treated EHM. Treatment of EHM with concentrations of DEX ranging from 5 to 500 nM (1.4-140 ng ml-1) for 48 h suppressed O2- release in response to phorbol myristate acetate in a dose-dependent fashion. Similarly, DEX significantly suppressed hyphal damage caused by EHM as measured by colorimetric MTT assay. Both GM-CSF (5 ng ml-1) and IFN-gamma (1.2 ng ml-1) added at day 0 to the EHM together with DEX (500 nM) significantly enhanced O2- release and percentage hyphal damage, preventing the DEX-induced suppression of EHM function. Thus, GM-CSF and IFN-gamma prevented the deleterious effects of DEX on antifungal activity of EHM against Aspergillus suggesting a potential therapeutic role in patients at risk for or suffering from invasive aspergillosis.

Abstract

Hepatosplenic candidiasis (HSC) or chronic disseminated candidiasis is an increasingly recognized problem in patients with cancer. Whether patients with HSC should continue to receive antineoplastic therapy, which may cause neutropenia with the risk for progressive HSC or breakthrough fungemia, can be a major dilemma. Patients with HSC at the National Cancer Institute continue antineoplastic therapy, when possible during antifungal therapy for HSC, despite repeated bouts of neutropenia. Therefore, whether this strategy resulted in breakthrough fungemia or progression of HSC was investigated.All patients consecutively treated at the National Cancer Institute at the Warren-Grant Magnuson Clinical Center from 1982-1992 for HSC were prospectively studied for therapeutic and outcome variables of antifungal and antineoplastic management. Each case was summarized on a time-event line to quantify the duration of simultaneous periods of antineoplastic therapy and antifungal therapy (AFT).Sixteen patients (median age, 22 years) with HSC were studied. Eleven patients had relapsed tumor and 5 had newly diagnosed tumor. During antifungal therapy for HSC, 12 of 16 patients were neutropenic for a median of 10 days (range, 6-91 days) and 11 were profoundly neutropenic for a median of 13 days (range, 1-55 days). Hepatosplenic candidiasis was successfully treated with complete antifungal response in 12 patients and a partial response in 2; 2 patients continued to receive AFT. No patient had breakthrough fungemia and two patients had progression of HSC, only one episode of which occurred during neutropenia.Hepatosplenic candidiasis in patients with cancer may be treated successfully under careful observation through repeated courses of chemotherapy-induced neutropenia without progression of hepatosplenic candidiasis or breakthrough fungemia.

Abstract

Children with the acquired immune deficiency syndrome (AIDS) and cytomegalovirus (CMV) retinitis may not complain of symptoms despite the presence of advanced sight-threatening disease. Although little data exist regarding CMV retinitis in this population, the treatment of this disease may be difficult because of frequent, extensive recurrences after reduction of drug dose from induction to maintenance levels. The authors reported the results of the use of combined ganciclovir and foscarnet for treatment of recurrent CMV retinitis in three children with AIDS.Three children with recurrent CMV retinitis were treated with combined ganciclovir and foscarnet administered intravenously. All patients initially received induction dosages of ganciclovir followed by maintenance therapy, at which time they experienced reactivation of their disease. The dosing regimen for induction with the combined therapy was foscarnet (60 mg/kg every 8 hours) and ganciclovir (5 mg/kg daily for 3 weeks). Maintenance with combined therapy consisted of foscarnet (90 mg/ kg daily) and ganciclovir (5 mg/kg daily).All patients showed complete healing of the retinitis during the first 3 weeks of combined therapy. Median survival after initiation of combined therapy was 15 weeks (range, 12-33 weeks). None of the children experienced reactivation of CMV retinitis during combined therapy with ganciclovir and foscarnet. Combined therapy was well tolerated in all patients without major side effects. No patient required discontinuation or interruption of either drug during combined therapy.Children with recurrent CMV retinitis may not report visual symptoms, which can delay therapeutic intervention. Therefore, recurrent disease in children should be treated aggressively to avoid potentially devastating visual loss. A combination of ganciclovir and foscarnet appears to be a safe and effective therapeutic option for treatment of recurrent CMV retinitis in children with AIDS. This approach causes no additional toxic reactions and may provide improved long-term control of recurrent CMV retinitis in children.

Abstract

The effects of recombinant human macrophage colony-stimulating factor (M-CSF) on antifungal activity of human monocytes (MNC), MNC-derived macrophages (MDM), and rabbit pulmonary alveolar macrophages (PAM) against Aspergillus fumigatus were studied. MNC-induced hyphal damage was augmented by incubation with M-CSF (P = .027); PAM-induced hyphal damage was moderately enhanced by M-CSF (P = .046). Phagocytosis of Aspergillus conidia by MDM and PAM was strongly enhanced by M-CSF (P < .01). MNC pretreated with M-CSF exhibited enhanced superoxide anion production in response to PMA (P = .026). This effect was not associated with increased levels of mRNA transcripts of the components of NADPH oxidase, the enzyme responsible for superoxide anion production. M-CSF augments antifungal activity of mononuclear phagocytes against both conidia and hyphae of Aspergillus fumigatus partly by enhancement of oxidation-dependent mechanisms and may have an important immunomodulatory role in prevention and treatment of invasive aspergillosis in leukopenic patients.

Abstract

Levels of human immunodeficiency virus type 1 (HIV-1) DNA and quinolinic acid were examined in areas of the central nervous system (CNS) and lymphoid organs (LN) from 5 AIDS patients with no clinically apparent CNS compromise (group I), 7 with CNS opportunistic diseases (group II), and 8 with HIV encephalopathy (group III). The brains from patients with HIV encephalopathy not only contained higher levels of HIV-1 DNA (cerebrum, P < .01; cerebellum, P < .05) as assessed by quantitative polymerase chain reaction but also showed a higher rate of viral pol region mutations suggestive of zidovudine or didanosine resistance than brains from patients in group I or II (P < .01). CNS quinolinic acid concentrations were significantly higher in group II and III patients than in group I (P = .03), even though quinolinic acid levels in LN were comparable among the 3 groups. These data suggest that CNS inflammatory changes associated with HIV encephalopathy may be triggered by a local productive HIV-1 infection within the CNS.

Abstract

Patients with chemotherapy-induced granulocytopenia for neoplastic diseases and those receiving cyclosporin A plus corticosteroids for prevention and treatment of organ transplant rejection are two immunologically distinct patient populations with high risks for development of invasive pulmonary aspergillosis. In order to compare the pathogenesis of aspergillosis in these two high-risk populations and to further characterize the role of cyclosporin A in development of pulmonary aspergillosis, we studied the patterns of infection and inflammation in two clinically applicable rabbit models of invasive pulmonary aspergillosis. There were striking differences in the patterns of infection and inflammation of invasive pulmonary aspergillosis according to the type of underlying immune defect. Among rabbits challenged with the same intratracheal inoculum, there was a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% mortality for invasive pulmonary aspergillosis in profoundly granulocytopenic rabbits in comparison with a 100% survival in rabbits immunosuppressed with cyclosporin A plus methylprednisolone (CsA+MP). Lesions of pulmonary aspergillosis in granulocytopenic rabbits consisted predominantly of coagulative necrosis, intraalveolar hemorrhage, and scant mononuclear inflammatory infiltrate. By comparison, pulmonary foci in rabbits immunosuppressed by CsA+MP consisted mainly of neutrophilic and monocytic infiltrates, inflammatory necrosis, and scant intraalveolar hemorrhage. There was extensive infiltration by hyphae with angioinvasion in granulocytopenic rabbits, whereas conidia in various stages of germination predominated in CsA+MP treated animals in which there was a paucity of hyphae or angioinvasion. Extrapulmonary disease predominated in granulocytopenic rabbits. Methylprednisolone was the major immunosuppressive drug in rabbits treated with CsA+MP. Cyclosporin A alone did not increase the progression of pulmonary aspergillosis and did so only when used chronically with methylprednisolone.

Abstract

Using a rapid automated enzymatic assay, we prospectively investigated serum D-arabinitol (DA), a biochemical marker of invasive candidiasis, in a large population of high-risk patients to determine its potential diagnostic, therapeutic, and prognostic significance in invasive candidiasis.A total of 3,223 serum samples were collected from 274 patients with cancer. Serum DA concentrations were determined in coded serum samples analyzed by rapid enzymatic assay. Creatinine also was analyzed in the same system to determine a serum DA and creatinine ratio (DA/Cr). The sensitivity, specificity, correlation with therapeutic response, and prognostic significance were analyzed for all patient study groups.A DA/Cr of > or = 4.0 mumol/L per mg/dL was detected in 31 (74%) of all 42 cases of fungemia and 25 (83%) of the 30 cases of the subset of persistent fungemia. Elevated DA/Cr was detected in 4 (40%) of 10 patients with tissue-proven, deeply invasive candidiasis and negative blood cultures (eg, hepatosplenic candidiasis or localized abscess) and 7 (44%) of 16 cases of deep mucosal candidiasis (eg, esophageal candidiasis). Elevated serial DA/Cr levels also were detected in persistently febrile and granulocytopenic patients requiring empirical amphotericin B. Among 26 assessable cases of fungemia, abnormally elevated DA/Cr values were detected in 14 (54%) before, 10 (38%) after, and 2 (8%) simultaneously with the first microbiologic report of fungemia. The trends of serial DA/Cr values correlated with therapeutic response in 29 (85%) of 34 patients with assessable cases of fungemia, decreasing in 8 (89%) of 9 patients with clearance of fungemia and increasing in 21 (84%) of 25 patients with persistence of fungemia. Among the 34 assessable patients with fungemia, mortality was directly related to the trend of serial DA/Cr determinations over time: 71% among fungemic patients who had persistently elevated or increasing DA/Cr, and 18% among the fungemic patients who had resolving DA/Cr or never had elevated DA/Cr (P < 0.01).Rapid enzymatic detection of DA in serially collected serum samples from high-risk cancer patients permitted detection of invasive candidiasis, early recognition of fungemia, and therapeutic monitoring in DA-positive cases. Serially collected serum DA determinations complement blood cultures for improving detection and monitoring therapeutic response in patients at risk for invasive candidiasis.

Abstract

Human immunodeficiency virus (HIV) infection in children can be complicated by the development of cardiac disease. Decreased left ventricular function has been temporally associated with the use of zidovudine (azidothymidine; AZT) in adults with HIV and has been associated with changes in cardiac muscle mitochondria in animal models. This study was done in an attempt to determine whether the cardiac disease is related to the antiretroviral therapy or to progressive HIV infection.We retrospectively reviewed echocardiograms, clinical records, and laboratory data from 137 HIV-infected children who were being treated by the Pediatric Branch, National Cancer Institute, and who were receiving AZT or didanosine, both drugs, or no antiretroviral therapy.Despite correction of the echocardiographic results for HIV disease severity with markers such as CD4+ lymphocyte count, time since infection, mode of acquisition of HIV, and age, children who were treated with AZT had a lower average fractional shortening than those who were not treated with AZT (p < 0.00001). There was a nonlinear relation between days of AZT use and this There was a nonlinear relation between days of AZT use and this decrease in fractional shortening. The odds that a cardiomyopathy would develop was 8.4 times greater in children who had previously used AZT than in those who had never taken AZT (95% confidence interval, 1.7 to 42.0). Didanosine was not associated with the development of a cardiomyopathy.Treatment of HIV-infected children with AZT may be associated with the development of a cardiomyopathy; didanosine does not appear to increase the risk of cardiomyopathy. The continued use of AZT in a child in whom a cardiomyopathy develops should be carefully assessed, and all children receiving AZT should be followed by serial cardiac examination and echocardiograms.

Abstract

To study the relationships between stage of HIV disease, reflected by CD4+ lymphocyte percentages and p24 antigen levels, and HIV-associated central nervous system (CNS) abnormalities, measured by computed tomography (CT) brain-scan ratings and neurobehavioral tests.Consecutive case series.Government medical research center.Eighty-six previously untreated children with symptomatic HIV-1 disease.CD4% measures correlated significantly with overall CT brain-scan severity ratings (r = -0.45; P < 0.001) as well as with its component parts (cortical atrophy, white matter abnormalities, and intracerebral calcifications); they were of comparable magnitude for vertically and transfusion-infected children. CD4% measures were also associated with the general level of cognitive function (r = 0.32; P < 0.005). Furthermore, patients with detectable serum p24 antigen levels (n = 39) had CT brain scans that were more abnormal than patients with undetectable p24 levels (n = 20; CT abnormality ratings of 21.3 versus 35.9; P < 0.02); similar differences were found for the cortical atrophy and calcification ratings. p24 levels also correlated with the overall CT brain-scan severity rating (r = 0.34; P < 0.01).Degree of CT brain-scan abnormality and level of cognitive dysfunction were significantly associated with the stage of HIV-1 disease, as reflected by either CD4 leukocyte measures or elevations of p24 antigen. The relation between the CT brain-scan lesions and markers of HIV disease (both CD4 and p24) suggest that these CNS abnormalities are most likely associated with HIV-1 infection, and further support the hypothesis that the interaction between systemic disease progression and CNS manifestations is continuous rather than discrete.

Abstract

Infectious complications represent significant challenges for children with cancer and those infected with HIV. Although both have similarities in the disease- and treatment-related alterations in host defences, there are significant differences that can have an impact on the approach to treatment and prevention of the dominant infectious complications. An important difference is that children with cancer readily recover from neutropenia. Thus, the immune deficits are interspersed with intervals of immunological recovery. On the other hand, children with HIV infection do not appreciably recover from the progressive, immunological changes associated with the underlying HIV infection. The loss of cellular and humoral immunity is generally not reversible, and thus the risk of infection only increases over time. Bacteria constitute the predominant pathogen for paediatric cancer patients but invasive mycoses, viruses and parasitic infections are emerging as important pathogens. In paediatric cancer patients, strategies have been directed at altering or suppressing the endogenous colonization patterns of pathogenic bacteria. The success of this approach has been limited and at the expense of selecting for antibiotic-resistant bacterial infections. Children with HIV infection are at risk of developing a wide spectrum of pathogens. Strategies for infection prevention in the HIV setting have been directed at specific organisms, generally using more specific antimicrobial agents and with greater success.

Abstract

In order to develop new approaches to treatment of infections due to Pseudallescheria boydii, the in vitro antifungal activity of amphotericin B alone and in combination with miconazole, itraconazole, and fluconazole was studied. Combinations of amphotericin B and antifungal azoles were synergistic, additive, or indifferent in their interaction against P. boydii. Antagonism was not observed.

Abstract

Inoculum size is a critical variable in development of methods for antifungal susceptibility testing for filamentous fungi. In order to investigate the influence of different inoculum sizes on MICs of amphotericin B, 5-fluorocytosine, itraconazole, and miconazole, 32 clinical isolates (8 Aspergillus fumigatus, 8 Aspergillus flavus, 5 Rhizopus arrhizus, 8 Pseudallescheria boydii, and 3 Fusarium solani isolates) were studied by the broth microdilution method. Four inoculum sizes were studied: 1 x 10(2) to 5 x 10(2), 1 x 10(3) to 5 x 10(3), 1 x 10(4) to 5 x 10(4), and 1 x 10(5) to 5 x 10(5) CFU/ml. The National Committee for Clinical Laboratory Standards reference method for antifungal susceptibility testing in yeasts was modified and applied to filamentous fungi. The inoculum was spectrophotometrically adjusted, and all tests were performed in buffered medium (RPMI 1640) at pH 7.0 with incubation at 35 degrees C for 72 h. MICs were read at 24, 48, and 72 h. Amphotericin B showed a minimum effect of inoculum size on MICs for all species with the exception of P. boydii (P < 0.05). A significant effect of inoculum size on MICs was observed with 5-fluorocytosine, for which there was an increase of more than 10-fold in MICs against all Aspergillus spp. between inoculum concentrations of 10(2) and 10(4) CFU/ml (P < 0.001). For itraconazole, the results showed a more species-dependent increase of MICs, most strikingly for R. arrhizus and P. boydii. Miconazole, which was tested only with P. boydii, did not demonstrate a significant effect of inoculum size on MICs. In summary, the effect of inoculum size on MICs for filamentous fungi was dependent upon the organism and antifungal compound tested. Thus, among antifungal compounds, itraconazole and 5-fluorocytosine demonstrated significant inoculum effects, while amphotericin B and miconazole showed comparatively minimum inoculum effects against pathogenic filamentous fungi. Moreover, among filamentous fungi, P. boydii and R. arrhizus exhibited the greatest inoculum effect.

Abstract

Pulmonary infiltrates in neutropenic hosts with invasive aspergillosis are due to vascular invasion and hemorrhagic infarction. In order to measure the effect of antifungal compounds on this organism-mediated tissue injury, we monitored the course of pulmonary infiltrates by serial ultrafast computerized tomography (UFCT) in persistently granulocytopenic rabbits with experimental invasive pulmonary aspergillosis. The course of pulmonary lesions measured by serial UFCT scans was compared with those measured by conventional chest radiography, histopathological resolution of lesions, and microbiological clearance of Aspergillus fumigatus. Treatment groups included either amphotericin B colloidal dispersion in dosages of 1, 5, and 10 mg/kg of body weight per day intravenously or conventional desoxycholate amphotericin B at 1 mg/kg/day intravenously. Therapeutic monitoring of pulmonary lesions by UFCT demonstrated a significant dose-response relationship. Lesions continued to progress in untreated controls, whereas lesions in treated rabbits initially increased and then decreased in response to antifungal therapy in a dosage-dependent manner (P < or = 0.05 to P < or = 0.005, depending upon the groups compared). This same trend of resolution of lesions in response to antifungal therapy was also demonstrated by postmortem examination and by microbiological clearance of the organism. These data indicated that amphotericin B colloidal dispersion at 5 and 10 mg/kg/day exerted a more rapid rate of clearance of lesions than conventional amphotericin B. UFCT was more sensitive than conventional chest radiography in detecting lesions due to invasive pulmonary aspergillosis (P < 0.05 to P < 0.005, depending upon the groups compared). These findings establish a correlation among UFCT-defined lesions, microbiological response, and resolution of pathologically defined lesions in experimental invasive pulmonary aspergillosis. Serial monitoring of UFCT-defined lesions of aspergillosis provides a novel system for determining the antifungal response of organism-mediated tissue injury.

Abstract

We report a case of disseminated intravascular coagulopathy, apparently caused by exposure to granulocyte colony-stimulating factor (G-CSF). The medical records of patients treated for more than 30 consecutive days with subcutaneously administered G-CSF were reviewed for the occurrence of thrombocytopenia or coagulation abnormalities. New-onset thrombocytopenia with a platelet count less than 100 x 10(9) cells/L (< 100,000 cells/mm3) developed in 9 of 23 patients (39%) after a median of 11 weeks of treatment with G-CSF at dosages between 1 and 10 micrograms/kg per day.

Abstract

Polymorphonuclear neutrophils (PMNs) are the major host defense against pseudohyphae, the invasive form of Candida species. We studied the effects of granulocyte colony-stimulating factor (G-CSF) and interferon-gamma (IFN-gamma) on the PMN-induced damage of pseudo-hyphae of Candida albicans, Candida tropicalis, and Candida parapsilosis in vitro by using two antifungal assays: a modified limiting dilution assay and a colorimetric metabolic 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. PMNs from healthy volunteers were incubated with either G-CSF (100-10,000 U/ml) or IFN-gamma (10-5000 U/ml) or buffer at 37 degrees C for 90 min and their capacity to damage nonopsonized pseudohyphae was then measured. C. tropicalis appeared to be the most susceptible species, whereas C. parapsilosis showed the highest rate of resistance to PMN damage. G-CSF (500-10,000 U/ml) and IFN-gamma (100-1000 U/ml) enhanced the antifungal activity of PMNs against C. albicans pseudo-hyphae (P < .01 and P < .05). Among the others, G-CSF enhanced PMN-induced damage of C. parapsilosis at concentrations 500-10,000 U/ml (P < .05), whereas it enhanced damage of C. tropicalis only at 10,000 U/ml (P < .01). IFN-gamma (100-1000 U/ml)-primed PMNs also caused augmented damage of C. parapsilosis (P < .05) but not of C. tropicalis at the same concentrations. Species-dependent differences exist in the responses of PMNs to Candida pseudohyphae and G-CSF as well as IFN-gamma are important immunomodulators of phagocytic host defenses against them.

Abstract

We characterized 27 episodes of fungemia in 22 children infected with the human immunodeficiency virus (HIV). Fungemia in these patients presented as a community-acquired infection in the setting of outpatient total parenteral nutrition or intravenous antibiotic therapy through a chronically indwelling central venous catheter (CVC). Fungemia developed only in patients with CVCs (P < .001). Non-albicans Candida species, Torulopsis glabrata, Rhodotorula rubra, and Bipolaris spicifera constituted 52% of all causes. Fungemia was detected early, within a median of 2.4 days after the onset of new fever, which permitted prompt administration of amphotericin B (mean dosage, 0.7 mg/[kg.day]; median duration, 19 days). CVCs were removed in 23 (85%) of the episodes. We conclude that fungemia in HIV-infected children often presents as a community-acquired infection, is frequently due to newly emerging opportunistic fungi, and can be managed, with a high level of success (95% survival with no posttherapeutic sequelae), by early diagnosis, prompt initiation of amphotericin B therapy, and removal of the CVC.

Abstract

Cytomegalovirus (CMV) infection is common in patients infected with human immunodeficiency virus. Hemorrhagic cystitis and tubulointerstitial nephritis have been recognized as complications of CMV infection, and these complications lead to hematuria and compromised renal function. We describe a case of CMV infection of the ureters in a child with vertically acquired human immunodeficiency virus infection; the child presented with severe suprapubic pain, and prolonged macroscopic hematuria and intermittent acute renal failure developed subsequently.

Abstract

To evaluate the clinical significance of computed tomographic brain scan abnormalities observed in children with symptomatic human immunodeficiency virus disease.Eighty-seven previously untreated children with symptomatic human immunodeficiency virus type 1 disease.General levels of cognitive functioning, obtained from age-appropriate intelligence tests, and social-emotional behavior were correlated with computed tomographic brain scan abnormality ratings.A significant relation between computed tomographic brain scan abnormalities and cognitive dysfunction as well as aberrant behavior was found, which appeared stronger in (younger) vertically infected children compared with transfusion-infected patients. Calcifications, independent from the degree of brain atrophy, were associated with significantly greater delays in neurocognitive development.Computed tomographic brain scan abnormalities, even when mild, were of clinical significance, suggesting that human immunodeficiency virus-associated central nervous system compromise is a continuous process and that scans may be helpful at baseline in defining patients at risk and for monitoring them during therapy.

Abstract

To compare the efficacy of ceftazidime and imipenem monotherapy for fever and neutropenia, and to determine whether fewer antimicrobial modifications (additions or changes) are required by the broader-spectrum agent, imipenem.Adult and pediatric patients undergoing chemotherapy for solid tumors, leukemias, or lymphomas were randomized to receive open-label ceftazidime or imipenem on presentation with fever and neutropenia. Success with or without modifications of the initial antibiotic was defined as survival through neutropenia; failure was death due to infection. Comparisons were based on numbers of modifications made to each monotherapy during the course of neutropenia, in patients stratified as having unexplained fever or a documented infection.Among 204 ceftazidime and 195 imipenem recipients, the overall success rate with or without modification was more than 98%, regardless of initial antibiotic regimen. Modifications occurred in half of all episodes, primarily in patients with documented infections on either monotherapy. Antianaerobic agents were more frequently added to ceftazidime (P < .001), but addition of other antibiotics, including vancomycin and aminoglycosides, was similar between the two monotherapy groups. Imipenem therapy was associated with significantly greater toxicity, manifested by Clostridium difficile-associated diarrhea and by nausea and vomiting, which required discontinuation of imipenem in 10% of recipients.Ceftazidime and imipenem are both effective in the management of fever and chemotherapy-related neutropenia, provided that modifications are made in response to clinical and microbiologic data that emerge during the course of neutropenia. Imipenem, despite its broader antimicrobial spectrum, does not significantly decrease the overall need for antibiotic modifications and is more often complicated by gastrointestinal toxicity.

Abstract

Sera from patients with systemic infections caused by the opportunistic fungus Trichosporon beigelii have been shown to cross-react with anticryptococcal antibodies. We quantitatively compared the amounts of antigen produced and examined the expression of O-acetyl epitopes from 35 strains of T. beigelii isolated from deep and superficial infections. By counterimmunoelectrophoresis, 10 of 10 isolates from deep infections were positive for polysaccharide, compared with 7 of 13 isolates from superficial infections (P = 0.02). All 23 strains tested were positive for polysaccharide when screened by immunodot. By enzyme immunoassay, the cross-reactive antigen produced by deep isolates (n = 9) had a mean titer of 1:5,500. In contrast, superficial isolates (n = 22) produced significantly less antigen than the deep isolates (P < 0.001), with a mean titer of 1:700. Isolates from environmental sources (n = 3) were similar to the superficial isolates, with a mean titer of 1:600. The mean concentrations +/- standard errors of cross-reactive polysaccharide released by deep isolates and superficial isolates were 3.09 +/- 0.44 and 1.74 +/- 0.30 micrograms/ml, respectively, when measured by rocket immunoelectrophoresis (P = 0.02). O-Acetyl epitopes were detected on polysaccharide from 8 of 9 strains of T. beigelii isolated from deep sources, while only 2 of 12 superficial isolates expressed detectable O-acetyl epitopes (P = 0.01). Thus, while all isolates of T. beigelii tested were capable of producing glucuronoxylomannan-like cross-reactive antigen, pathogenic isolates produced significantly more antigen than superficial or environmental isolates. Furthermore, significantly more pathogenic isolates than superficial or environmental isolates expressed antigen that was O acetylated.

Abstract

To investigate the effect of HIV disease on the receptive and expressive language of children and the relationship between CT scan brain abnormalities and language functioning.Thirty-six children (mean age, 5.5 years; range, 1 through 10 years; 75% vertical transmission; 58% classified as encephalopathic) with symptomatic HIV infection and 20 uninfected siblings (mean age, 7.8 years; range, 3 through 15 years) were administered an age-appropriate comprehensive language test assessing both receptive and expressive language (Reynell Developmental Language Scales or Clinical Evaluation of Language Fundamentals--Revised). Each HIV-infected child had a CT scan of the brain as part of the baseline evaluation, which was rated independently and blindly by two neurologists, for presence and severity of brain abnormalities using a semiquantitative rating system.Expressive language was significantly more impaired than receptive language in the overall sample of HIV-infected children. The encephalopathic children scored significantly lower than the non-encephalopathic children, however, the degree of discrepancy between mean receptive and expressive language scores was not significantly different between these two groups. The uninfected sibling control group did not have a significant discrepancy between receptive and expressive language, and they scored significantly higher than the infected patient group. Greater severity of CT scan abnormalities was significantly correlated with poorer receptive and expressive language functioning in the overall HIV-infected sample and a higher discrepancy between receptive and expressive language in the encephalopathic group.Pediatric HIV disease is associated with differential receptive and expressive language functioning in which expressive language is significantly more impaired than receptive language. The sibling data and CT scan correlations suggest that the observed language impairments are associated with the direct effects of HIV-related central nervous system disease.

Abstract

The distinction between upper versus lower urinary tract infection in patients with candiduria is a commonly encountered and therapeutically important diagnostic dilemma. Candida casts have been reported in the urine of several individual case reports of human renal candidiasis. The specificity of Candida casts would identify unequivocally a patient with upper urinary tract disease. Little is known, however, about the sensitivity and the formation of Candida casts. We therefore studied the diagnostic yield, methods for detection and pathogenesis of Candida cast formation in serially collected urine specimens from immunologically intact and granulocytopenic rabbit models of haematogenous disseminated candidiasis. Refractile blastoconidia and pseudohyphae of Candida encased in the granular matrix were seen on wet mounts while Candida stained a brilliant red in the fuschia pink tubular matrix on periodic acid Schiff (PAS) stained cytopathology filters. Among 24 rabbits with disseminated candidiasis, 11 (46%) had Candida casts detectable by wet mount and PAS-stained urine filters in comparison to none of 10 non-infected immunologically normal controls (P = 0.014). Fifteen (70%) of 21 episodes of Candida casts were detected within the first 3 days of infection, indicating possible utility in the early diagnosis of renal candidiasis. No Candida casts were detected in the urine of granulocytopenic rabbits, possibly due to the rapid destruction of tubules and abrogation of cast formation. This absence of detectable Candida in eight infected granulocytopenic rabbits differed significantly from that of 24 non-granulocytopenic infected rabbits, in which Candida casts were detected in 11 (46%) (P = 0.029). Candida cast formation occurred predominantly in the cortex. Histopathological examination demonstrated invasion of Candida into the glomerular tufts and peritubular capillaries, followed by development of Candida casts in the proximal and distal tubules, respectively. Detection of renal Candida casts may be a useful diagnostic marker in distinguishing upper versus lower urinary tract candidiasis.

Abstract

To further understand human host defenses against Trichosporon beigelii, functional responses were investigated of polymorphonuclear leukocytes (PMNL) and elutriated human monocytes (EHM) to this opportunistic fungal pathogen. There was significantly less PMNL phagocytosis (P < .001) and killing (P < .001) of T. beigelii isolates than of Candida albicans. However, levels of superoxide anions generated by PMNL in response to T. beigelii and C. albicans were comparable. Pretreatment of PMNL with granulocyte colony-stimulating factor or interferon-gamma (IFN-gamma) did not significantly enhance fungicidal activity. Killing of T. beigelii by EHM also was significantly impaired compared with killing of C. albicans (P < .001). However, pretreatment of EHM with macrophage colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, or IFN-gamma all resulted in enhanced fungicidal activity. Thus, phagocytosis and killing of T. beigelii by PMNL and EHM are significantly less efficient than that of C. albicans. However, monocytes may be more important in the control of Trichosporon species than previously shown.

Abstract

Because cyclosporin A (CsA) is extensively used as an immunosuppressive agent, its effects on phagocytic defenses against Aspergillus fumigatus were studied in vitro and ex vivo. After incubation with 10 to 250 ng of CsA per ml at 37 degrees C for 60 min, polymorphonuclear leukocytes (PMNs) exhibited unaltered superoxide anion (O2-) production in response to phorbol myristate acetate and N-formylmethionyl leucyl phenylalanine, whereas > or = 500 ng/ml significantly suppressed it (P < 0.01). Moreover, at < 250 ng of CsA per ml, PMNs exhibited no change in their capacity to damage unopsonized hyphae of A. fumigatus compared with controls, whereas at > or = 250 ng/ml, CsA suppressed the function (P < 0.01). Although neither CsA (250 ng/ml) nor hydrocortisone (10 micrograms/ml) suppressed PMN O2- production in response to phorbol myristate acetate and N-formylmethionyl leucyl phenylalanine, combination of the two agents reduced the function compared with that at the baseline (P < 0.05). Incubation of monocytes with 100 ng of CsA per ml for 1 or 2 days suppressed their antihyphal activity. No essential change in phagocytic activity of monocyte-derived macrophages (MDMs) against A. fumigatus conidia, tested as the percentage of phagocytosing MDMs and average number of MDM-associated conidia, was detected after 2 or 4 days of incubation with 10 to 1,000 ng of CsA per ml. Furthermore, in rabbits treated with CsA (up to 20 mg/kg of body weight per day intravenously for 7 days), neither O2- production and hyphal damage caused by PMNs or monocytes against hyphae nor phagocytosis of conidia by pulmonary alveolar macrophages was significantly suppressed. Thus, these results demonstrated that CsA within therapeutically relevant concentrations does not suppress antifungal activity of phagocytes except that of circulating monocytes. However, it may induce significant immunosuppression of phagocytes' antifungal function at relatively high concentrations in vitro, especially when combined with corticosteroids.

Abstract

Didanosine, a purine analogue with antiretroviral activity, is used in the treatment of human immunodeficiency virus disease. Associated toxic effects of didanosine include pancreatitis, peripheral neuropathy, and retinopathy. The retinal lesions associated with didanosine therapy were studied in a 6-year-old girl with acquired immunodeficiency syndrome. Gross examination disclosed multiple well-circumscribed depigmented lesions in the midperipheral retina. Microscopic examination of these lesions showed multiple areas of retinal pigment epithelial (RPE) loss, some surrounded by areas of hypertrophy or hypopigmentation of the RPE. Partial loss of the choriocapillaris and neurosensory retina were also noted in areas of diseased RPE. Transmission electron microscopy showed numerous membranous lamellar inclusions and cytoplasmic bodies in the RPE cells. These data show that didanosine primarily affects the RPE and that the choriocapillaris and overlying neurosensory retina are also dystrophic in areas of RPE loss.

Abstract

Didanosine has demonstrated promising antiviral activity and a tolerable toxicity profile in short term studies. We describe a cohort of HIV-infected children who were treated for a prolonged period of time with didanosine.Children (6 months to 18 years of age) with symptomatic HIV infection or an absolute CD4 count < 0.5 x 10(9) cells/L, received oral didanosine at doses between 20 mg/m2 to 180 mg/m2 every 8 hours. Clinical, immunological, and virological parameters were assessed at least every 2 months. The pharmacokinetics of didanosine were evaluated in 85 patients.Previously untreated children (n = 51) and children who had received prior antiretroviral therapy (n = 52) were enrolled in the study (median time on study 22.6 months; range 2 to 48). The long-term administration of didanosine was well tolerated and no new toxicities were observed. The absolute CD4 count increased by > or = .05 x 10(9) cells/L in 28 of 87 (32%) of patients after 6 months of therapy. Responses were also sustained in 41% of these children after 3 years of therapy. Children entering the study with a CD4 count > 0.1 x 10(9) cells/L (n = 51) had a marked survival advantage (P = .00002) with an estimated survival probability after 3 years of 80% compared to 39% for children with lower CD4 counts. Although the area under the curve of didanosine increased proportionally with the dose, there was considerable interpatient variability at each dose level. There was no apparent relationship between surrogate markers of clinical outcome and plasma drug concentration.Didanosine was well tolerated with chronic administration, and toxicities were uncommon and usually reversible. In 41% of patients, the CD4 count increased and was maintained at the higher level even after years of treatment.

Abstract

Human monocytes are important effector cells in host defenses against Aspergillus hyphae, and as elutriated monocytes (EHM) they may be transfused in large quantities to leukopenic patients with invasive aspergillosis. The antifungal activity of EHM against Aspergillus hyphae was compared with that of polymorphonuclear leukocytes (PMNL). The effects of granulocyte-macrophage colony-stimulating factor (GM-CSF) and interferon-gamma (IFN-gamma) on superoxide anion (O2-) release and on hyphal damage caused by EHM against unopsonized A. fumigatus hyphae was investigated. EHM had antihyphal activity comparable to that of PMNL. GM-CSF significantly augmented O2- release by EHM in response to PMA. Also, both GM-CSF and IFN-gamma significantly enhanced the antifungal activity of EHM compared with untreated controls. Thus, EHM have demonstrable antifungal activity against Aspergillus hyphae that may be increased by GM-CSF and IFN-gamma, suggesting their potential therapeutic role in immune reconstitution of effector cells.

Abstract

During the past decade, an increasing spectrum of pathogenic Zygomycetes fungi have caused infections in humans. The preponderance of these deeply invasive infections have been caused by members of the order Mucorales. However, deeply invasive zygomycoses due to genera of the order Entomophthorales (Conidiobolus species and Basidiobolus species) have seldom been reported. We describe a granulocytopenic patient with pulmonary and pericardial zygomycosis due to Conidiobolus incongruus, describe this organism's susceptibility to antifungal agents, characterize its diagnostic microbiological characteristics, and review previously reported cases of deeply invasive zygomycosis due to Conidiobolus species. In immunocompromised patients, C. incongruus is an uncommon but highly invasive fungal pathogen that may be resistant to amphotericin B and can be distinguished from other Zygomycetes fungi by characteristic mycological features.

Abstract

We examined the relationship between the concentrations of zidovudine in plasma given by continuous intravenous infusion to human immunodeficiency virus-positive pediatric patients and a surrogate marker of outcome (measured by the increase in the number of CD4-positive T cells) as well as drug-mediated toxicity (change in granulocyte count). The return of CD4-positive T cells was most strongly related to the number of these cells present at the start of therapy. Drug concentration data added little explanatory power to this relationship, indicating that the effect of zidovudine was near maximal throughout the range of concentrations examined. The change in granulocyte count was significantly correlated with zidovudine concentration both from weeks 1 through 8 and from weeks 8 through 12. These findings imply that it may be wise to stratify phase I antiretrovirus drug trials for the entry level of CD4-positive T cells if pharmacodynamic relationships with this marker as the dependent variable are to be sought. Continued efforts need to be made to derive quantitative relationships between drug exposure and measures of both efficacy and toxicity so that the maximal amount of information is derived from small phase I studies.

Abstract

The amount of human immunodeficiency virus type 1 (HIV-1) in various tissues was investigated by polymerase chain reaction (PCR) in 16 patients with end-stage HIV-1 infection and 7 patients with symptomatic but less advanced disease. During postmortem study of the 16 end-stage patients, HIV-1 DNA was found most often in lymph nodes and the spleen (both 100%), lung (93.8%), and colon (87.5%). Biopsied lymph nodes from the 7 symptomatic patients contained substantially higher copy numbers of HIV-1 RNA and DNA than did peripheral blood mononuclear cells (PBMC). Plasma viral RNA levels correlated significantly with the amount of HIV-1 RNA in PBMC (r2 = .86, P = .0025) but not with the level of viral RNA in lymph nodes in patients with symptomatic HIV-1 infection. These data suggest that although lymph nodes represent the main site for HIV-1 infection and replication, the level of circulating viral burden may not be solely determined by the magnitude of active HIV-1 replication in lymph nodes.

Abstract

Four dimensions of psychological adaptation of 101 parents of HIV-infected children were examined. Heightened anxiety, depression, and anticipatory grief were associated with child's age at diagnosis, parent's HIV status, and parent's relationship to the child. Parents at higher risk for psychological distress were identified, and an optimum time point for intervention is suggested.

Abstract

As part of a phase I/II trial in children infected with human immunodeficiency virus, we studied the pharmacokinetics of zidovudine and didanosine administered as single agents and in combination. Zidovudine (60 to 180 mg/m2 per dose) was given orally every 6 hours, and didanosine (60 to 180 mg/m2 per dose) every 12 hours. Pharmacokinetic samples were obtained from 54 patients and the area under the plasma concentration-time curve (AUC) was estimated by means of a previously defined limited sampling strategy. Follow-up blood samples were obtained after 4 and 12 weeks of treatment. The mean AUC for zidovudine ranged from 4.8 mumol.hr per liter at 60 mg/m2 to 11.0 mumol.hr per liter at the 180 mg/m2 level, and increased in proportion to the dose. The mean AUC for didanosine ranged from 2.8 mumol.hr per liter (60 mg/m2) to 8.0 mumol.hr per liter (180 mg/m2), with a wide interpatient variability. The AUCs of zidovudine and didanosine remained unchanged when the agents were administered in combination. There was no significant change in the AUCs of either drug after 4 and 12 weeks in comparison with those on day 3 of therapy. However, there was greater interpatient and intrapatient variability with didanosine than with zidovudine. These observations have implications for the future utility of therapeutic drug monitoring with these agents.

Abstract

Itraconazole and amphotericin B were compared by using a newly developed model of invasive pulmonary aspergillosis in rabbits immunosuppressed with methylprednisolone and cyclosporin A (CsA). Both itraconazole at 40 mg/kg (given orally) and amphotericin B at 1 mg/kg (given intravenously) had in vivo antifungal activity in comparison with controls. At these dosages, amphotericin B was more effective than itraconazole in reducing the tissue burden (log10 CFU per gram) of Aspergillus fumigatus (P < 0.05) and the number of pulmonary lesions (P < 0.01). However, there was considerable variation in the near-peak concentrations of itraconazole in plasma (median, 4.15 micrograms/ml; range, < 0.5 to 16.8 micrograms/ml) and a strong inverse correlation between concentrations of itraconazole in plasma and the tissue burden of A. fumigatus. An inhibitory sigmoid maximum-effect model predicted a significant pharmacodynamic relationship (r = 0.87, P < 0.001) between itraconazole concentrations in plasma and antifungal activity as a function of the tissue burden of A. fumigatus. This model demonstrated that levels in plasma of greater than 6 micrograms/ml were associated with a significantly greater antifungal effect. Levels in plasma of less than 6 micrograms/ml were associated with a rapid decline in the antifungal effect. Itraconazole, in comparison with amphotericin B, caused a twofold elevation of CsA levels (P < 0.01) but was less nephrotoxic (P < 0.01). This study of experimental pulmonary aspergillosis demonstrated that amphotericin B at 1 mg/kg/day was more active but more nephrotoxic than itraconazole at 40 mg/kg/day, that itraconazole increased concentrations of CsA in plasma, and that the antifungal activity of itraconazole strongly correlated with concentrations in plasma in an inhibitory sigmoid maximum-effect model. These findings further indicate the importance of monitoring concentrations of itraconazole in plasma as a guide to increasing dosage, improving bioavailability, and optimizing antifungal efficacy in the treatment of invasive pulmonary aspergillosis.

Abstract

We investigated the psychosocial adjustment of school-aged, human immunodeficiency virus-positive children and factors associated with level of adjustment. Participants were primarily transfusion-infected children living in middle-class families. We administered measures of depression, anxiety, and self-concept to children, and measures of behavior problems, social functioning, personality characteristics, and life events to parents. An index of disease stage was also collected. Children reported experiencing low levels of depressive and anxious affect and generally felt positively about themselves. By contrast, parents saw their children as more anxious and less socially active than respective standardization samples. A greater than expected proportion of these children, as reported by their parents, scored in the maladaptive range on measures of social functioning, anxiety, and conduct problems. Experience of adversive life events and progression of the disease were associated with more behavioral and social problems. Findings are discussed in terms of their generalizability and implications for future research.

Abstract

To determine the safety, tolerance, pharmacokinetics, and antimycobacterial activity of orally administered clarithromycin in children with acquired immunodeficiency syndrome and disseminated Mycobacterium avium complex (MAC) infection.Phase I study with a 10-day pharmacokinetic phase followed by a 12-week continuation therapy phase.Twenty-five patients with a median age of 8.3 years were enrolled. Ten were receiving zidovudine and 13 were receiving didanosine at the time of enrollment.Clarithromycin suspension was administered to each patient at one of three dose levels: 3.75, 7.5, and 15 mg/kg per dose every 12 hours. Clarithromycin and antiretroviral pharmacokinetics were measured during single-drug and concurrent-drug administration. Clinical and laboratory monitoring was performed biweekly.Clarithromycin was well tolerated at all dose levels. Plasma clarithromycin concentrations increased proportionately with increasing doses, and significant pharmacokinetic interactions were not observed during concurrent administration with zidovudine or didanosine. Decreases in mycobacterial load in blood were observed only at the highest clarithromycin dose level. Decreased susceptibility to clarithromycin developed rapidly (within 12 to 16 weeks) in the majority of MAC strains isolated from study patients.

Abstract

The prevalence of acquired immunodeficiency syndrome (AIDS) is steadily increasing among American children. The dental needs of these patients are significant. This study evaluated the oral health of forty children being treated for HIV-infection at the National Institutes of Health (NIH). Eight of twenty-two patients in primary dentition (36 percent) had baby bottle tooth decay (BBTD). These cases required extensive dental restoration usually under general anesthesia. Tooth development was delayed in 31 percent of patients. Candidiasis was the most common soft tissue abnormality, found in 35 percent of children. Preventive and therapeutic dental programs should be instituted to meet the special needs of pediatric AIDS patients.

Abstract

We investigated the safety and efficacy of amphotericin B colloidal dispersion (ABCD) for the treatment of invasive pulmonary aspergillosis in persistently granulocytopenic rabbits. Treatment groups included ABCD in dosages of 1, 5, and 10 mg/kg/day intravenously or conventional desoxycholate amphotericin B (DAmB) at 1 mg/kg/day intravenously. Antifungal activity was directly related to increasing dosage of ABCD as determined by the concentration of Aspergillus fumigatus organisms in lungs and the frequency of hemorrhagic pulmonary lesions. At 5 and 10 mg/kg/day, there was a significant reduction in the tissue burden of A. fumigatus as measured by percent culture-positive lobes and CFU per gram of tissue (P < or = 0.001), whereas at 1 mg/kg/day measured by percent culture-positive lobes and CFU per gram of tissue (P < or = 0.001), whereas at 1 mg/kg/day the tissue burden of A. fumigatus was not significantly different from that in untreated controls. Microbiological clearance was significantly greater at 1 mg of DAmB per kg per day than at 1 mg of ABCD per kg per day (P < or = 0.001). There was no difference in microbiological clearance of bronchoalveolar lavage fluid among the treatment groups as measured by CFU per milliliter. As determined by survival, ABCD at 5.0 mg/kg/day was more effective than DAmB at 1.0 mg/kg/day and ABCD at 10 mg/kg/day. ABCD at 10 mg/kg/day was more nephrotoxic than the lower dosages of ABCD and resulted in higher mortality. Impairment of glomerular filtration developed as a direct function increasing the ABCD dosage (r = 0.77; P < 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Developed a Q-sort procedure to assess social, emotional, and motivational behavior associated with central nervous system disease among 180 HIV-infected pediatric patients. These ratings were factor analyzed and scales were derived based on the factor structure. Younger (M age = 1.03 years) patients with HIV-associated encephalopathy were rated as more apathetic and nonsocial in their behavior than nonencephalopathic younger patients. Older (M age = 7.8 years) encephalopathic patients had significantly higher scores on scales measuring depression, autism, and irritability compared to nonencephalopathic patients from this age group. A subgroup (26 patients) showed a significant decrease in these elevated scores after a 6-month course of AZT.

Abstract

Zidovudine and didanosine are both beneficial for the treatment of human immunodeficiency virus (HIV) infection in children. Because disease progression and toxicity often limit their long-term use as single agents, new approaches to using nucleoside analogues are necessary to improve current antiretroviral therapy.We conducted a phase I-II study to evaluate the tolerance, pharmacokinetics, and antiviral activity of the combination of zidovudine and didanosine in children with HIV infection. Sixty-eight children who were either previously untreated or who had manifested hematologic toxicity on full-dose zidovudine were enrolled. Eight dose combinations were studied in the previously untreated children, with doses of zidovudine ranging from 90 to 180 mg/m2 every 6 hours and doses of didanosine ranging from 90 to 180 mg/m2 every 12 hours.Fifty-four previously untreated HIV-infected children were enrolled in this part of the study, of whom 49 remained in the study for a minimum of 24 weeks. For children with previous zidovudine-related hematologic toxicity, three dose levels with zidovudine at 60 mg/m2 every 6 hours orally and didanosine ranging from 90 to 180 mg/m2 every 12 hours orally were used. A total of 14 children were enrolled in this part of the study, and 12 remained on therapy for at least 24 weeks. No evidence of new or enhanced toxicity was observed in either group. After 24 weeks, the median CD4 cell count for all patients increased from 331 to 556 cells/mm3 (P = .01). For the previously untreated group, the median increase in CD4 counts was from 386 to 726 cells/mm3 (P = .003). The median p24 antigen concentration (in those with a detectable level at baseline) decreased from 95 to < 31 pg/mL (p < .001). The geometric mean titer of HIV in plasma decreased from 83.1 to 2.7 tissue culture infectious doses/mL (P = .001).The combination of zidovudine and didanosine was well-tolerated at doses as high as those used in single agent therapy. Potent in vivo antiviral activity was observed. Combination therapy with nucleoside analogues may be an important approach to optimizing the use of these agents in the treatment of HIV infection.

Abstract

A model of primary pulmonary aspergillosis in rabbits was developed to reproduce the persistent levels of profound granulocytopenia and the histopathologic features of bronchopneumonia, vascular invasion, and hemorrhagic infarction encountered in humans. D-mannitol was detectable in bronchoalveolar lavage fluid by gas-liquid chromatography/mass spectroscopy, and galactomannan was measurable in serum by latex agglutination immunoassay. A pharmacokinetically distinctive unilamellar vesicle formulation of liposomal amphotericin B, 5 mg/kg/day intravenously, compared with high-dose conventional desoxycholate amphotericin B, 1 mg/kg/day intravenously, was more effective in preventing nephrotoxicity, increasing survival, reducing the number of viable organisms, and decreasing tissue injury due to Aspergillus organisms. Thus, D-mannitol in lavage fluid and galactomannan in serum may be useful markers of pulmonary aspergillosis, and liposomal amphotericin B was significantly more effective and safer than desoxycholate amphotericin B for treatment of pulmonary aspergillosis in profoundly granulocytopenic rabbits.

Abstract

Assessed longitudinally the effects of HIV infection and zidovudine on the adaptive behavior of 25 children with symptomatic disease (M age = 5.3 years; range = 1-12; 52% classified as encephalopathic) by parent report using the Vineland Adaptive Behavior Scales. Patients also were evaluated with an age-appropriate intelligence test and Q-sort Behavioral Rating Scale. Before treatment, encephalopathic children exhibited greater impairments in adaptive behavior than those without encephalopathy. After 6 months of zidovudine, all behavioral domains (communication, daily living, socialization) except for motor skills showed overall significant improvement. Children with or without encephalopathy showed a similar degree of change. Improvements in adaptive behavior correlated with increases in cognitive ability and decreases in severity of aberrant social-emotional behavior.

Abstract

In order to further understand serum D-arabinitol (DA) as a marker for the diagnosis of disseminated candidiasis and for monitoring response to antifungal therapy, we studied the serum levels of this Candida carbohydrate metabolite by rapid automated enzymatic assay in rabbits with experimental disseminated candidiasis. The enzymatic reaction steps were performed on a standard automated clinical chemistry analyser. As a correction for renal impairment, data were expressed as serum D-arabinitol/creatinine ratio (DA/Cr). Serum creatinine concentrations were determined from the same sample with the same instrument, thereby allowing rapid determination of the DA/Cr within one laboratory. The DA/Cr was determined in 321 samples from 132 rabbits. The mean serum DA/Cr in 31 normal non-infected rabbits was 1.51 +/- 0.2 microM mg-1 dl-1. Among 84 rabbits with disseminated candidiasis and pre-terminal samples, there was a direct correlation between DA/Cr and tissue concentration of Candida albicans (r = 0.80; P < 0.001). A threshold of elevated DA/Cr (> or = 3.0 microM mg-1 dl-1) was evident in rabbits with a tissue concentration of C. albicans > or = 3 x 10(4) colony forming units (CFU) g-1. Elevated DA/Cr was detected in 48 (89%) of 54 rabbits at a C. albicans tissue concentration of > or = 3 x 10(4) CFU g-1 vs. one (3%) of 30 rabbits with < 3 x 10(4) CFU g-1 (P < 0.0001). Among all 101 rabbits with disseminated candidiasis, an elevated DA/Cr was detected at any point during infection in 60 (92%) of 65 rabbits having a C. albicans tissue concentration > or = 3 x 10(4) CFU g-1 vs. 13 (36%) of 36 rabbits with < 3 x 10(4) CFU g-1 (P < 0.0001). The relationship between the tissue response to antifungal therapy and change in DA/Cr was then further analysed. Ten (91%) of 11 rabbits with a tissue-proven response to antifungal therapy (defined as > or = 10(2)-fold reduction of CFU g-1 in comparison to untreated controls) had a > 50% reduction in elevated DA/Cr levels. By comparison, 10 (83%) of 12 treated rabbits with no response to therapy had persistently elevated DA/Cr levels (P < 0.001). These findings provide an experimental basis for understanding the patterns of expression of serum DA in disseminated candidiasis and further indicate that serial DA/Cr measurements may be useful for diagnosis and therapeutic monitoring of disseminated candidiasis.

Abstract

The interrelationships of patterns of change and variability between baseline and after 6 months of anti-retroviral therapy in neurocognitive, brain imaging, and immune measures were studied in 77 children with symptomatic HIV disease. Overall improvement in CNS structure/function after 6 months of anti-retroviral therapy was limited; new intracerebral calcifications tended to occur and old ones tended to progress in young children with vertically acquired HIV infection, despite treatment. Substantial inter-individual differences in change were however observed. Factors which explained part of the variance in the magnitude and direction of change were baseline structural and functional abnormalities, rating of degree of CNS penetration of the drug protocol, and concurrent changes on other variables. These preliminary data suggest that CNS specific effects of therapies as well as pretreatment status of CNS function/structure need to be taken into consideration when evaluating future trials of anti-retroviral therapy for children with symptomatic HIV infection.

Abstract

Trichosporon beigelii is an emerging fungal pathogen, which is morphologically characterized by blastoconidia, arthroconidia and hyphae. The non-hyphal forms of T. beigelii germinate to form hyphae in plasma in vitro and in tissues in vivo, suggesting possible pathophysiological significance of this process. Little is known, however, about the mechanisms of germination of T. beigelii. We therefore studied relevant biochemical and pharmacological factors that may regulate germination of T. beigelii. Germination was significantly enhanced by temperature at 37 degrees C, chemically defined cell culture media such as RPMI-1640, plasma, physiological pH, N-acetylglucosamine and proline. N-acetylglucosamine was equivalent to proline in inducing germination. Germination was suppressed by high concentrations of glucose, increasing inocula, low pH, and amphotericin B at achievable serum concentrations. Thus, many of the factors regulating germination of T. beigelii appear to be similar to those for Candida albicans.

Abstract

Invasive aspergillosis recently has been encountered in adults and children with human immunodeficiency virus (HIV) infection even without known risk factors, such as neutropenia or corticosteroid therapy. Macrophages play a significant role in the host defenses against Aspergillus organisms by ingesting conidia and preventing their germination to hyphae. The antifungal activity of peripheral blood monocyte-derived macrophages (MDM) from 19 HIV-infected children was compared with that of 16 normal controls. The phagocytic activity of patients' MDM, measured as percentage of phagocytosis, was significantly decreased compared with normal donors (P = .014). In addition, the inhibitory activity of MDM on germination of intracellular A. fumigatus conidia was significantly impaired in patients compared with normal controls (P = .016). There was no significant difference in the defects between patients with lower or higher CD4 lymphocyte counts. Impairment of antifungal activity of macrophages may contribute to the susceptibility of HIV-infected patients to aspergillosis.

Abstract

To identify factors that may aid in the diagnosis and treatment of patients with malignant neoplasms in whom hepatic abscesses develop.Retrospective review of medical records.Thirty-seven oncology patients in whom hepatic abscesses developed at the National Cancer Institute, Bethesda, Md, between June 1954 and October 1989.Among 37 cancer patients, bacterial abscesses developed in 17 and fungal abscesses developed in 20. Among the patients with bacterial abscesses, 12 (71%) had a solid-tissue malignant neoplasm, 10 (59%) had a prior invasive procedure, and six (35%) had prior chemotherapy. In comparison, among the patients with fungal abscesses, 15 (75%) had a hematologic malignant neoplasm and five (25%) had a solid-tissue malignant neoplasm (P2 = .014). Two patients with fungal abscesses (10%) had a prior invasive procedure (P2 = .004) and 19 (95%) had prior chemotherapy (P2 < .0001). As compared with fungal abscesses, bacterial abscesses were larger (P2 < .00001) and fewer (P2 = .004). Antibiotics and percutaneous or surgical drainage effectively treated bacterial abscesses. Amphotericin B usually eradicated hepatic fungal infections.The results of this study reveal the importance of the clinical setting in the diagnosis of hepatic abscesses in cancer patients. Aggressive treatment of these abscesses is indicated and is frequently effective.

PERSPECTIVES ON THE USE OF CYTOKINES IN THE MANAGEMENT OF INFECTIOUS COMPLICATIONS OF CANCERCLINICAL INFECTIOUS DISEASESRoilides, E., Pizzo, P. A.1993; 17: S385-S389

Abstract

Treatment of neoplastic diseases is followed by a variety of infectious complications. Neutropenia and functional defects of phagocytes are common consequences of cancer and its treatment and contribute to an increased susceptibility to infections. Cytokines with hematopoietic growth stimulatory and/or immunoenhancing properties, such as granulocyte-macrophage colony-stimulating factor (GM-CSF), granulocyte colony-stimulating factor (G-CSF), interleukin-3, interferon-gamma, macrophage colony-stimulating factor, interleukin-1, and interleukin-6 have been shown to either have clinical utility in patients with cancer and neutropenia or offer the promise to do so. GM-CSF and G-CSF, for example, have been shown to reduce the incidence of fever and infectious complications in patients with cancer and neutropenia. The role of cytokines for the treatment of defined infections (e.g., invasive mycoses) is under investigation.

Abstract

Neutrophils (PMNs) are a critical line of defense against Aspergillus fumigatus infection. Increased frequency of invasive aspergillosis has been observed in patients receiving corticosteroids, suggesting a deleterious effect of these compounds on PMN antifungal function. To investigate this hypothesis and to determine the potential preventive utility of granulocyte colony-stimulating factor (G-CSF) and gamma interferon (IFN-gamma), the effects of hydrocortisone (HCS) and dexamethasone (DXS) on PMN-induced damage of Aspergillus fumigatus hyphae were studied with or without pretreatment of PMNs with G-CSF and IFN-gamma. PMNs treated with HCS (> or = 3,000 microM) or DXS (> or = 10 microM) during a 2-h colorimetric tetrazolium metabolic assay (using methylthiotetrazolium) showed suppressed percentage of hyphal damage (P < 0.02). In addition, both HCS (> or = 30 microM) and DXS (> or = 1 microM) significantly suppressed oxidative burst measured as superoxide anion release by PMNs in response to opsonized and nonopsonized hyphae as well as to N-formylmethionyl leucyl phenylalanine. Pretreatment of PMNs with G-CSF (4,000 U/ml) and/or IFN-gamma (100 and 1,000 U/ml) for 90 min prevented the suppression of hyphal damage that occurred in the presence of HCS (3,000 microM; P < 0.01) or DXS (10 microM; P < or = 0.001). G-CSF (4,000 U/ml) and IFN-gamma (100 U/ml) combined had an additive effect on increasing the antifungal activity of HCS-treated but not of DXS-treated PMNs compared with IFN-gamma alone (P = 0.015). Thus, these findings reveal that corticosteroids impair PMN function in response to A. fumigatus and that G-CSF and IFN-gamma prevent this impairment.

Abstract

Cancer patients who suffer prolonged durations of fever and neutropenia are at high risk for developing serious infections. This article reviews the initial management of these fevers, subsequent modifications of the initial empirical regimens (both empirical changes in the antibiotic regimen and those changes directed at specific sites of infection that may become apparent during the course of prolonged neutropenia), and the potential impact of hematopoietic cytokines on future management of prolonged fever and neutropenia.

Abstract

In an effort to improve outcome in patients with metastatic or high-risk localized Ewing's sarcoma family of tumors (ESF) and rhabdomyosarcoma (RMS), we explored the role of consolidation therapy with total-body irradiation (TBI) plus autologous bone marrow transplantation (ABMT).Ninety-one patients were entered onto one of three consecutive protocols from 1981 to 1986. Induction therapy consisted of four or five cycles of vincristine, doxorubicin, and cyclophosphamide (VAdriaC); in the earlier series, patients received one or two cycles with dactinomycin instead of doxorubicin. Irradiation of the primary site was used for local control. Patients who attained a complete response (CR) to induction therapy were eligible for consolidation with 8 Gy TBI plus VAdriaC and ABMT.Nineteen patients were ineligible for consolidation after failing to achieve or maintain a CR following induction therapy; all 19 are dead of disease. Seven eligible patients elected to forgo consolidation; three of seven are long-term event-free survivors. Sixty-five patients received consolidation therapy; 20 of 65 are long-term event-free survivors. A local control rate of 83% was achieved using radiation therapy as the primary modality of local control. Patients with metastatic disease at diagnosis fared substantially worse than did patients with localized tumors (6-year event-free survival [EFS] rate, 14% v 38%; two-sided P [P2] = .008).Consolidation of patients with metastatic or high-risk localized pediatric sarcomas with 8 Gy TBI plus ABMT has failed to improve the outcome of this group of patients. Metastatic disease at diagnosis continues to confer the poorest prognosis. New therapeutic strategies are needed to consolidate more effectively the remissions that can be achieved in the majority of these patients.

Abstract

Qualitative analysis of 100 consecutive computed tomographic (CT) studies of the brain in children with symptomatic but untreated acquired immunodeficiency syndrome was performed. After excluding children with associated medical illnesses that might confound the diagnosis of encephalopathy or alter brain structure, an abnormality of at least one of the measures of ventricular size, cortical atrophy, white matter attenuation (leukoaraiosis), or cerebral calcification was found in 86% of the patients studied. Ventricular enlargement was the most common abnormality, followed by cortical atrophy, leukoaraiosis, and cerebral calcification. Cerebellar atrophy was an unexpected but relatively common finding in 12% of the children. Sixty-five percent of the children were encephalopathic at the time of evaluation. All 16 children with cerebral calcification were encephalopathic and had acquired human immunodeficiency virus (HIV) through vertical transmission. Encephalopathic children were significantly younger and had significantly greater abnormality ratings on each CT measure when compared with the nonencephalopathic children. Discriminant analysis using age and the qualitative CT measures was applied as a method to identify the presence of encephalopathy. CT measures proved to have a specificity and a sensitivity of only 76%. We conclude that abnormalities of cerebral structure are seen in a high percentage of children symptomatic with HIV. Although most of the children are encephalopathic, CT abnormalities are seen in children without encephalopathy, suggesting presymptomatic brain disease. The presence of cerebral calcification on CT suggests in utero infection with HIV and the presence of encephalopathy.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Several studies have demonstrated significantly higher frequency and more rapid detection of candidemia with blood culture methods performed by lysis-centrifugation (LC) in comparison with other techniques. Little is known, however, about the ability of LC blood culture methods to detect tissue-proven invasive candidiasis. We therefore investigated the sensitivity of LC blood cultures in the detection of tissue-proven invasive candidiasis. Between 1985 and 1991, invasive candidiasis was detected in 41 (5.1%) of 803 autopsies at the Clinical Center of the National Institutes of Health (Bethesda, MD, USA). Cases were classified as single-organ (SO) candidiasis (n = 20) and as disseminated candidiasis (DI) (n = 21). Patients with DI were more likely than those with SO to have a hematologic malignancy (71% vs 15%, P < 0.001) and to have gastrointestinal mucosal candidiasis (76% vs 25%, P = 0.003). LC detected fungemia in 16 (43%) of all 37 cases with blood cultures. When analyzed by classification, Candida spp. were isolated from blood in 11 (58%) of 19 patients with DI and in five (28%) of 18 patients with SO (P = 0.13). When analyzed by number of organs infected, blood cultures were positive in seven (78%) of nine patients with > 3 organs infected by Candida in comparison to five (28%) of 18 patients with one organ infected (P = 0.024). The mean recovery time for Candida in blood cultures was 2.6 days in DI and 3.2 days in SO (P = 0.017). There was no difference in colonies of organisms per LC tube between patients with DI and those with SO.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

The number of immunocompromised hosts has dramatically increased in recent years. The primary reason for this increase has been the intensification of antineoplastic therapy for the treatment of various malignancies and the explosive spread of human immunodeficiency virus infection. Although the treatment and prevention of many infections have been improved with the rational use of antimicrobial agents, ultimate success can be blunted by protracted impairment of essential host defenses or by the virulence of certain organisms.

Abstract

Human immunodeficiency virus type 1 (HIV-1) isolates from children receiving long-term therapy with an alternating regimen of zidovudine and zalcitabine, or with didanosine monotherapy, were evaluated for resistance to zidovudine, zalcitabine, and didanosine, and for mutations known to be associated with zidovudine or didanosine resistance. HIV-1 from four of six patients receiving zidovudine with zalcitabine developed high-level resistance to zidovudine. A mutation in the HIV-1 reverse transcriptase that is highly associated with zidovudine resistance was identified in all four zidovudine-resistant posttherapy isolates. In contrast, none of the HIV-1 isolates from the seven patients receiving didanosine developed high-level resistance to this agent, despite the identification of a didanosine-associated mutation in six of these posttherapy isolates, although small decreases in sensitivity to didanosine were observed. These results indicate that nucleoside analog-associated mutations in HIV-1 occur frequently in children receiving long-term antiretroviral therapy and that alternating combination therapy does not prevent the development of resistance to zidovudine. They also suggest that there may be differences in the degree of resistance conferred by mutations that result from therapy with different nucleoside analogs. These findings underscore the need for studies to define the clinical importance of these mutations, and for treatment strategies to overcome the emergence of viral resistance in vivo.

Abstract

To define predictive or contributory risk factors for pancreatitis in human immunodeficiency virus-infected children receiving dideoxyinosine (ddI), the authors evaluated 95 children, 3 months to 18 years of age, who had received ddI at 60 to 540 mg/m2 per day for a mean of 56 weeks. Pancreatitis developed in 7 patients (7%) but resolved in all upon withdrawal of ddI. Neither age, sex, nor CD4 count at study entry was predictive of pancreatitis, but pancreatitis appeared more likely to develop in hemophiliacs than in other patients (4 of 23 vs 3 of 72). Pancreatitis developed only in patients who received ddI at the highest dose levels (7 of 60 patients who received ddI at a dose > or = 360 mg/m2 per day vs 0 of 35 patients who received < or = 270 mg/m2 per day). Patients in whom pancreatitis developed had received a higher mean daily dose of ddI than patients with normal amylase and lipase levels throughout the study (348 mg/m2 vs 282 mg/m2), but no relationship with the cumulative dose or the duration of ddI therapy was observed. Although a statistically significant relationship between ddI plasma concentration (area under the curve) and pancreatitis was not conclusively demonstrated, as the number of patients in whom pancreatitis actually developed was small, such a relationship may have been obscured.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Invasive aspergillosis is a serious fungal infection caused by the proliferation and invasion of Aspergillus hyphae in tissue. Neutrophils (PMNs) are the most important line of defense against Aspergillus hyphae. To investigate the role of granulocyte colony-stimulating factor (G-CSF) and gamma interferon (IFN-gamma) against Aspergillus fumigatus, we studied the effects of the two cytokines on the oxidative burst and the capacity of normal human PMNs to damage hyphae of the organism. G-CSF enhanced PMN oxidative burst measured as superoxide anion (O2-) production in response to N-formylmethionyl leucyl phenylalanine, serum opsonized hyphae, and nonopsonized hyphae by 75, 37, and 24%, respectively, compared with control PMNs (P < 0.015). IFN-gamma also induced increases of 52, 71, and 96%, respectively, in response to the same stimuli (P < 0.006). In addition, the capacity of PMNs to damage hyphae as measured by the 3-4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MMT) colorimetric metabolic assay was significantly enhanced by G-CSF and IFN-gamma (P < 0.01 and < 0.05, respectively). The enhancement was achieved irrespective of serum opsonization of the hyphae, suggesting upregulatory actions of the two cytokines on signal pathways specific for opsonized and nonopsonized hyphae. The combination of the two cytokines exhibited an additive effect at the higher concentrations compared with the effects of the cytokines alone (P < 0.05). Pretreatment of PMNs with protein synthesis inhibitors showed that IFN-gamma activates PMN function through transcriptional regulation, whereas the effect of G-CSF does not require new proteins. These in vitro effects suggest modulatory roles for G-CSF and IFN-gamma in the host defense against Aspergillus hyphae irrespective of serum opsonization and a potential utility of the cytokines as adjuncts for the prevention and possible treatment of invasive aspergillosis.

Abstract

Protective immunity to human immunodeficiency virus (HIV) was examined in 228 serial sera from 58 HIV-infected children before and during antiretroviral therapy. Binding antibodies to putative protective V3 epitopes of HIV-1IIIB and HIV-1MN were investigated by a peptide ELISA, and neutralizing antibodies by inhibition of HIV-1MN cell-free viral infection. No difference in binding of total IgG or IgG subclasses was observed between patients with mild (group A) or advanced disease (group B). However, group A patients were more likely to possess neutralizing antibody titers > or = 225 (P = .040 after adjustment for CD4). This threshold titer also predicted clinical outcome in patients with age-adjusted CD4 count > 10% of normal median. Patients with titers < 225 more frequently encountered major clinical events during follow-up than did patients with titers > or = 225 (P = .0028). Epitopes other than the linear V3 loop contribute to this protective immune response. Identification of these epitopes should assist immune therapy of AIDS and HIV vaccine development.

Abstract

Suramin is a polyanionic compound with potent antineoplastic properties. Because polymorphonuclear leukocytes (PMNs) are a crucial component of host defenses against bacteria and fungi, the effects of suramin on PMN function were studied in vitro. PMNs from healthy donors were incubated with concentrations of suramin of 1 to 1,000 micrograms/ml (within and exceeding the therapeutic range) for 30 min, and PMN functional parameters were subsequently assessed. Suramin had no effect on viability, chemotaxis to N-formylmethionyl leucyl phenylalanine, phagocytosis of Candida albicans, or superoxide anion production in response to phorbol myristate acetate and formylmethionyl leucyl phenylalanine. Fungicidal activity against C. albicans blastoconidia was unaffected at a suramin concentration of < 500 micrograms/ml, whereas at higher concentrations a slight suppression was observed (P = 0.04). Bactericidal activity against Staphylococcus aureus was significantly suppressed by concentrations of > or = 100 micrograms/ml (P < 0.01). Phagocytosis of S. aureus was also significantly impaired at > or = 10 micrograms/ml (P < 0.05). The presence of 10% human serum during pretreatment did not abrogate the suramin-induced suppression of bactericidal activity. Treatment of PMNs with granulocyte colony-stimulating factor (4,000 U/ml) for 30 min prior to the addition of suramin (250 micrograms/ml) improved the bactericidal defect (P = 0.02). The PMN functional impairment may be related to increased susceptibility to bacterial infections, and granulocyte colony-stimulating factor may improve the defect.

Abstract

We describe two patients with severe aplastic anemia in whom neutropenic enterocolitis developed while they were undergoing treatment at the National Institutes of Health. Both patients had progressive symptoms while receiving optimal medical management and both underwent and survived surgical intervention despite continued prolonged neutropenia in the perioperative period. This experience contrasts with six cases reported in the literature and suggests that surgery can be employed even in patients with profound neutropenia. Thus, in patients who remain persistently septic or who develop clinical deterioration despite medical management or who have other indications for surgical intervention, neutropenia should not be a contraindication to the appropriate or necessary procedure.

Abstract

In Brazil, 226 children with cancer presenting 299 episodes of fever and neutropenia (< or = 500/mm3) were treated with two consecutive empirical regimens. Regimen I-Cefoxitin Amikacin-Carbenicillin; and Regimen II Ceftriaxone-Amikacin. 67.0% of the patients had leukemias or lymphomas, documented infections occurred in 47.2%, superinfections occurred in 18.7% (Reg. I) and 17.8% (Reg. II) of the episodes. The most common agents identified in Reg. I and Reg. II were, respectively, Gram negative rods (55.0%) and Gram positive cocci (52.6%). The overall rate of success with modifications (Amphotericin B, Vancomycin, Clindamycin, Metronidazole) was higher in Reg. II (93.0%) than in Reg. I (84.0%). This study shows that the appropriate formula to maximize the successful treatment of children with cancer, fever and neutropenia in developing nations includes adherence to established principles of supportive care, utilizing the optimal antibiotic agents available in the country. It is important to promote the necessary modifications along the treatment having in mind the high index of resistant agents.

Abstract

In most centers treating cancer patients, significant progress has been made in permitting patients to survive even prolonged courses of neutropenia. This has resulted from a better understanding of the epidemiology of infection and the points during the clinical course when they pose a risk for the patient with prolonged neutropenia. Considerable benefit has been derived from the availability of more potent broad-spectrum antimicrobial agents and from organized strategies for when they should be initiated, how and when they should be modified, and for how long they should be continued. The possibility that the duration of neutropenia might be attenuated in patients receiving chemotherapy now seems real with the ever-expanding repertoire of cytokines and other biologic agents that augment the hematopoietic and immune systems. Coupled with the use of peripheral stem cell reconstitution or the insertion of genes into hematopoietic stem cells that might render them resistant to the cytocidal effects of certain chemotherapeutic agents, it now seems possible to envision regimens that might alter the consequences of neutropenia as we have come to know them. It is likely, therefore, as additional experience is garnered and as chemotherapy regimens are devised, that the optimal approach to the management of the patient with prolonged neutropenia will include the rational use of antibiotics together with cytokines and other biologicals. Hopefully, such regimens will permit the delivery of chemotherapy in a manner that might enhance its tumoricidal activity and improve the outcome of patients with cancer.

Abstract

To compare the frequency of infectious episodes or other problems occurring with an externalized catheter (Hickman) versus a subcutaneously implanted device (Port-a-Cath, Pharmacia, Piscataway, NJ) in cancer patients, we performed a prospective, randomized study in 100 cancer patients (age range, 5 to 74 years).Patients who were chemotherapy candidates and required an indwelling catheter were monitored prospectively and evaluated during the 180 days after the insertion of the catheter and again at time of study closure. The frequency of catheter use, reason for access, and any problems that might have been related to catheter use were noted. All data were collected prospectively and included the patient's age, sex, underlying malignancy, temperature, and leukocyte and absolute granulocyte counts at the time of catheter insertion and when complications occurred. The time to and reason for removal of the catheter, as well as any intercurrent infectious or mechanical problems, were also determined.Most of the infections that occurred were caused by gram-positive organisms, especially staphylococci or streptococci. A total of 22 complications (11 in each group) resulted in removal of the central line. Only one infection in the Hickman catheter group and four in the Port-a-Cath group led to removal of the central line. All other infectious episodes were successfully treated without removal of the catheters. The mean device life was 230 days for the Hickman catheter and 318 days for the Port-a-Cath (not significant).There were no differences between the two study groups regarding incidence of documented infections or mechanical or thrombotic complications.

Abstract

More than 250 children treated at our institution on antiretroviral treatment protocols have been monitored with brain imaging studies. We documented the occurrence and progression of aneurysms of major cerebral arteries in two children with advanced human immunodeficiency virus infection. In both cases these lesions remained clinically silent initially, despite progression to marked dilation.

Abstract

The use of empirical antimicrobial therapy has significantly reduced the morbidity and mortality associated with untreated infections in febrile neutropenic patients. This guideline describes clinical trials of the safety and efficacy of new antimicrobial drugs in this population of patients. Fever and neutropenia should be precisely defined in each protocol. Patients should be randomized to treatment with a new or active-control drug regimen, stratified on the basis of type of cancer and age, and treated until resolution--as defined in the protocol--is attained. Outcome should be assessed both for cases with a defined microbial etiology and for those without. Final microbiological outcome is important for cases with identified pathogens, but clinical outcome is paramount.

Abstract

Bone marrow suppression is the major dose-limiting toxic effect of zidovudine (azidothymidine; AZT) in children with human immunodeficiency virus infection. We evaluated the effect of subcutaneously administered granulocyte colony-stimulating factor (G-CSF) in pediatric patients whose absolute neutrophil count was less than 0.8 x 10(9)/L during AZT therapy despite dosage reductions to 120 mg/m2 every 6 hours. Nineteen patients between 6 months and 20 years of age were treated with AZT and G-CSF and monitored for 2 to 12 months. All had previously shown improvement while receiving AZT but had required dosage reduction or discontinuation. By using a sliding dosing schedule of G-CSF, we attempted to maintain the absolute neutrophil count between 1.5 and 5.0 x 10(9)/L. Administration of G-CSF resulted in a significant increase in the median leukocyte count (2.0 x 10(9)/L to 4.14 x 10(9)/L; p = 0.004), and the median absolute neutrophil count (1.02 x 10(9)/L to 2.96 x 10(9)/L; p = 0.0006). G-CSF was well tolerated, but mild thrombocytopenia developed in nine children. Administration of G-CSF and AZT was discontinued in two patients because of continuing neutropenia. With doses of G-CSF ranging from 1 to 20 micrograms/kg per day, 17 of 19 patients were able to tolerate AZT at a dose of 120 to 180 mg/m2 every 6 hours. We conclude that G-CSF therapy enables patients who have had AZT-related neutropenia to receive therapeutic doses of AZT.

Abstract

We reviewed the 22 cases of Mycobacterium avium-intracellulare (MAI) infection that occurred among 196 human immunodeficiency virus-infected children seen at the National Cancer Institute Pediatric Branch from December 1986 through April 1991, and an additional 65 charts from children with cultures negative for MAI. All patients with proven MAI were receiving antiretroviral therapy with zidovudine, dideoxyinosine, or a combination of zidovudine and dideoxycytidine. All patients had disseminated MAI infection, except one adolescent who had only evidence of localized lymphadenitis. All cases of MAI but one were diagnosed before death. The overall incidence of MAI was 11% in our patients but increased to 24% in patients whose absolute CD4 cell counts were < 100 cells/mm3. Symptoms most commonly associated with MAI infection included recurrent fever (86% of patients), weight loss or failure to thrive (64%), neutropenia (55%), night sweats (32%), and abdominal pain (27%). Children infected with MAI had a mean CD4 percentage of 2% (range, 0% to 7%) and a mean absolute CD4 count of 12 cells/mm3 (range, 0 to 48 cells/mm3), significantly lower than in the remainder of the clinic population or the group of children with cultures negative for MAI. Of 20 patients with MAI infection who were tested, 10 had measurable p24 antigen with a mean value 939 pg/ml (range, 77 to 3270 pg/ml) compared with 19 of 59 patients without MAI infection in whom the mean positive value was 413 pg/ml. There was no difference in survival time between those children with documented MAI infection (median survival time, 45.5 weeks) and those with similarly low CD4 counts and cultures negative for MAI (median survival time, 50.4 weeks). Future improvements in therapeutic options may make screening of pediatric human immunodeficiency virus-infected patients with low CD4 counts a reasonable plan.

Abstract

Didanosine has shown activity against the human immunodeficiency virus (HIV) in both children and adults. We prospectively assessed T-helper cell (Th) function as determined by in vitro interleukin-2 (IL-2) production in response to a panel of T-cell stimuli in 22 HIV-infected children before and during didanosine therapy and we correlated the incidence of opportunistic and recurrent bacterial infections with changes in p24 antigen and CD4 counts. Didanosine (270, 360, or 540 mg/m2/d) was administered orally for periods ranging from 8 to 40 weeks (mean, 24 weeks). Five of six asymptomatic patients (Centers for Disease Control P-1) compared with 6 of 16 symptomatic (P-2) patients exhibited improved Th function (greater than threefold increase in IL-2 production to at least 2 of the 4 stimuli) during therapy. Of 12 patients without infections during therapy, 9 (75%) showed improvement in Th function, compared with only 2 of 10 patients with infections (P = .03). Notably, the incidence of infections was not correlated with improvements in CD4 count or decreases in p24 antigen. Improvement in Th function during didanosine therapy is correlated with decreased incidence of infections. Assessment of Th function may provide an additional measurement of immunologic response to antiretroviral therapy.

Abstract

To determine the safety and pharmacokinetics of recombinant soluble CD4 (sCD4) administered by continuous intravenous infusion to children with symptomatic human immunodeficiency virus type 1 infection, we conducted a phase I study at the National Cancer Institute. Three dose levels of sCD4 were evaluated: 100, 300, and 1000 micrograms/kg per day. After an initial 12 weeks of treatment with sCD4 alone, dideoxyinosine at a dose of 90 mg/m2 every 8 hours was added and subjects were observed for an additional 12 weeks. Combination therapy was continued in patients in whom it was well tolerated. In addition to toxicity and pharmacokinetic monitoring, surrogate markers of antiviral activity were evaluated. Eleven children were enrolled in the study. During the 12 weeks of treatment with sCD4 alone, and during subsequent sCD4 plus dideoxyinosine combination therapy, no significant toxic reaction attributable to sCD4 or dideoxyinosine was encountered. Low-level anti-CD4 antibodies developed in two patients. Steady-state sCD4 levels increased proportionately at higher doses. The CD4 cell counts and serum p24 antigen levels did not provide evidence of antiviral activity. We conclude that sCD4 was well tolerated at doses up to 1000 micrograms/kg per day when administered by continuous intravenous infusion; however, evidence of in vivo antiviral activity was not observed in this study.

Abstract

Defective in vitro T helper cell (Th) function can occur in asymptomatic human immunodeficiency virus (HIV)-seropositive (HIV+) individuals. A characteristic, early finding is the loss of an in vitro response to recall antigens, such as influenza A virus (FLU), despite an intact Th response to alloantigen (ALLO). To determine whether suppressor cells and/or inhibitory factors could contribute to this HIV-associated Th immunodeficiency, coculture studies were performed using peripheral blood leukocytes (PBLs) from monozygotic twins, one of whom was HIV-infected (HIV+) and one of whom was uninfected (HIV-seronegative, HIV-). In vitro Th function was measured as interleukin 2 production or proliferation to FLU and ALLO. Two pairs of twins were repetitively studied. A single HIV+ individual with multiple samples of cryopreserved PBLs over 6 years (including a HIV- specimen) was also studied. PBLs from the HIV+, but not from the HIV-, individuals demonstrated defective in vitro Th function in response to FLU but not to ALLO. PBLs from HIV+ individuals could induce a similar defect in the Th function of syngeneic or autologous HIV- PBLs. This suppression was generated by CD4-depleted, but not by CD8-depleted, PBLs. A suppressive factor from CD8+ cells of HIV+ donors was generated by 24-hr unstimulated cultures of HIV+ PBLs. This factor inhibited FLU but not ALLO responses of autologous, syngeneic, or allogeneic HIV- PBLs. This suppressive effect could not be explained by HIV infection or replication during the culture period. These results demonstrate that selective abrogation of Th function to recall antigens in HIV+ individuals is associated with an inhibitory factor produced by CD8+ T cells.

Abstract

Traditional management of infectious complications, especially in immunocompromised hosts, has depended on the prompt initiation of therapy with broad-spectrum antibiotics. During the past several years, however, a number of cytokines (interleukins, hematopoietic growth factors, interferons) have been developed and produced by recombinant DNA technology, and preclinical and clinical studies of cytokines in immunocompromised hosts have begun. The data being generated suggest that certain cytokines can accelerate neutrophil and monocyte/macrophage production, enhance their function, and potentially decrease infectious complications. The role of these agents in both the prevention and treatment of infectious diseases represents an important research challenge and offers new approaches to the prevention and treatment of infection in immunocompromised hosts.

Abstract

Pulmonary complications, both infectious and noninfectious, are an important cause of morbidity in patients with various types of immunosuppression. The appropriate response to these clinical problems requires an understanding of pulmonary host defense and of the various types of systemic immunosuppression. Infectious and noninfectious pulmonary complications may vary according to the type of immunosuppression as well as to the degree and duration of immunosuppression. Appropriate clinical management also requires an understanding of the clinical problems commonly seen in specific groups of immunosuppressed patients and an understanding of the sensitivity, specificity, and potential complications associated with the available diagnostic approaches to those patients. Because respiratory disease in these patient groups may progress rapidly to respiratory failure, an expeditious evaluation based on the knowledge of likely causes of respiratory disease and prompt specific or empiric therapy are indicated. Specific sets of algorithms for the evaluation of both focal and diffuse pulmonary disease may facilitate such an evaluation. In addition, an aggressive approach to the prevention of pulmonary disease including immunization, prophylaxis, and immunomodulation (for example, colony stimulating factors) may be warranted in specific subgroups at risk.

Abstract

The effects of granulocyte colony-stimulating factor (G-CSF) and interferon-gamma (IFN-gamma) on the oxidative burst of neutrophils (PMNL) in response to blastoconidia and pseudohyphae of Candida albicans were assessed and compared with those in response to N-FMLP. G-CSF enhanced oxidative burst, as measured by superoxide production, in response to both FMLP and opsonized blastoconidia. The enhancement of oxidative burst in response to FMLP was significantly greater (P = .004) than that in response to blastoconidia (65% and 39%, respectively). G-CSF also enhanced oxidative burst in response to pseudohyphae. IFN-gamma enhanced oxidative burst in response to FMLP and opsonized blastoconidia by 53% and 50%, respectively. Moreover, IFN-gamma significantly enhanced oxidative burst in response to opsonized and nonopsonized hyphae by 86% and 65%, respectively. These results demonstrate that G-CSF and IFN-gamma enhance the oxidative burst of PMNL in response to both blastoconidia and pseudohyphae of C. albicans and suggest an immunomodulatory role of the two cytokines in the host defenses against this fungus.

Abstract

To determine the relationship between CD4 status and the P24 antigen level and survival in children infected with the human immunodeficiency virus.Cohort, case-control.Clinical Center at the National Institutes of Health, Bethesda, Md.One hundred forty-seven children infected with the human immunodeficiency virus enrolled in antiretroviral therapy protocols at the National Cancer Institute were reviewed and the relationships between CD4 counts, P24 antigenemia, and death were analyzed.None.The presence of a very low CD count, less than 21% of the lower limit of normal values for age (equivalent to 0.05 x 10(9)/L in an adult), was associated with a significantly increased risk of death within 2 years. Although the risk of death was highest for children with CD4 counts below this level and who had detectable P24 antigen levels, P24 antigenemia by itself contributed little to the prognostic value of the CD4 count alone. However, it was also notable that a group of children with low CD4 counts also experienced prolonged survival.The association between low CD4 counts and death suggests that the age-adjusted CD4 count should be used as a marker to guide therapeutic intervention. At the same time, the presence of a very low CD4 count alone should not be considered a reason for therapeutic nihilism.

Abstract

We classified 159 cases of rhabdomyosarcoma (RMS) according to the conventional scheme adopted by the World Health Organization and a modified conventional scheme established at the National Cancer Institute (NCI), Bethesda, Md. The major modification in the NCI scheme was the inclusion of compact round-cell RMS with scant myogenesis in the group of alveolar RMS despite lack of an alveolar architecture. These tumors were previously considered to be embryonal RMS, but their cytologic features are quite different from those seen in embryonal RMS and are indistinguishable from those encountered in alveolar RMS. These tumors are referred to as "solid alveolar RMS." Survival curves were constructed with the method of Kaplan-Meier and compared with the unstratified and stratified methods of Mantel-Haenszel (with stratification factors being stage, site, and age) and with the Cox regression analysis. Both histologic schemes showed a statistically significant prognostic value in unstratified analyses, but the NCI scheme demonstrated prognostic value even in stratified analyses and in the Cox regression analysis in our series of cases. The data indicate that the NCI scheme can serve as a highly predictive, independent prognostic factor in RMS and that the alveolar category should be expanded to include the solid round-cell RMS, even in the absence of a classic alveolar architecture.

Abstract

Patients with neoplastic diseases are predisposed to develop invasive fungal infections as the result of impairments of host defense mechanisms due principally to pharmacologic immunosuppression resulting from intensive cytotoxic chemotherapy, ablative radiation therapy, and corticosteroids. Candida species, Aspergillus species, and emerging opportunistic fungal pathogens comprise the principal etiologic agents of opportunistic mycoses in cancer patients. This paper reviews the recent progress, particularly during the year of 1991, in management of invasive fungal infections and the current problems of invasive mycosis, which confront patients with neoplastic diseases.

Abstract

Disseminated Trichosporon infection, an uncommon but emerging opportunistic mycosis due to Trichosporon beigelii, is frequently difficult to diagnose, refractory to treatment, and associated with a high attributable mortality. Models of disseminated and gastrointestinal Trichosporon infection were developed in persistently granulocytopenic rabbits. The patterns of infection resembled those of clinical disease, including cutaneous lesions, chorioretinitis, renal infection, pulmonary infection, and antigenemia cross-reactive with cryptococcal capsular polysaccharide. Antigenemia, an early manifestation of disseminated Trichosporon infection, originated in vivo from a fibrillar extracellular matrix. Trichosporon organisms disseminated from the gastrointestinal tract to visceral tissue in colonized immunosuppressed rabbits, whereas there was no dissemination from the gastrointestinal tract of otherwise normal rabbits. The antifungal triazoles, fluconazole and SCH 39304, were most active; maximum tolerated doses of amphotericin B and liposomal amphotericin B were ineffective. Trichosporon antigenemia declined in response to antifungal therapy. These findings contribute to improved understanding of the pathogenesis, diagnosis, and treatment of disseminated Trichosporon infection.

Abstract

Thirteen bacteremias and 25 nonbacteremic infections caused by Pseudomonas spp. occurred in 22 of 236 children with human immunodeficiency virus infection with a rate of infection of 0.098 (bacteremia, 0.030) per patient year. Four patients were neutropenic (less than 500/microliters). Central venous catheter (CVC)-related infections were most frequent (n = 20) followed by otitis externa (n = 6) and pneumonia (n = 5). Pseudomonas aeruginosa was the most common isolate and caused both CVC-related and CVC-unrelated infections, whereas other Pseudomonas spp. and Xanthomonas maltophilia were almost exclusively associated with CVC-related infections. The children who received appropriate therapy had a favorable outcome. In 7 CVC-related infections (35%) the catheter was removed. Pseudomonas spp. are of increasing importance in human immunodeficiency virus-infected children causing significant morbidity and increased hospitalization. These infections may be life-threatening if appropriate therapy is not vigorously initiated.

Abstract

Mycobacterium gordonae is only rarely a cause of infection despite its ubiquity in the environment. We describe an 11-year-old girl with disseminated infection due to M. gordonae whose course was complicated by renal failure requiring hemodialysis but who recovered after 15 months of chemotherapy. In a literature search we identified 23 additional cases of infection attributed to M. gordonae, with involvement of the lungs (eight), soft tissue (seven), the peritoneal cavity (three), the cornea (one), and with disseminated disease (five patients, including ours). Two patients were infected with human immunodeficiency virus. We assessed the patterns of infection characteristic of each site and the antibiotic sensitivities of the isolates. Adequate documentation of M. gordonae infection (e.g., amount of growth per culture, detection of specific biochemical characteristics, and confirmation of the organism's identity by a reference center) was lacking in many reports. M. gordonae should not automatically be dismissed as a contaminant when isolated from clinical material. Additional studies are required to establish the extent of this organism's pathogenic role.

Abstract

We describe a newly developed method of continuous intravenous infusion and simultaneous monitoring of plasma levels of investigational compounds in ambulatory untethered rabbits. Continuous infusion was administered by means of a portable programmable external micropump which permitted adjustable dosing. Simultaneous plasma pharmacokinetic monitoring during infusion was accomplished by dual silastic central venous catheters. The potential applications of the micropump infusion system as an alternative to current methods of continuous infusion in other species and in other studies are further discussed. This method provided a safe, reliable, and well-tolerated method of adjustable continuous intravenous infusion and simultaneous sampling of central venous blood in rabbits.

Abstract

To evaluate the safety, tolerance, and pharmacokinetics of fluconazole in children with neoplastic diseases, we studied fluconazole in 26 children, aged 5 to 15 years, with normal renal function who were receiving treatment for cancer. The patients received fluconazole, 2, 4, or 8 mg/kg per day for 7 days intravenously for a 2-hour period. Patients had no nausea or vomiting related to fluconazole; three patients had an asymptomatic rise in hepatic aminotransferase values after four to six doses (one patient at 2 mg/kg per day and two patients at 8 mg/kg per day), which returned to normal within 2 weeks after discontinuation of the drug. Fluconazole showed linear first-order kinetics over the dosage range tested and during multiple dosing. After the first dose, mean clearance was 22.8 +/- 2.3 ml/min, volume of distribution 0.87 +/- 0.06 L/kg, and terminal elimination half-life 16.8 +/- 1.1 hours. Similarly, after the last dose, clearance was 19.4 +/- 1.3 ml/min, volume of distribution 0.84 +/- 0.04 L/kg, and terminal elimination half-life 18.1 +/- 1.2 hours. Patients receiving their first fluconazole dose of 8 mg/kg achieved peak serum levels of 9.5 +/- 0.4 microgram/ml and trough levels of 2.7 +/- 0.5 microgram/ml 24 hours later, and an area under the serum concentration-time curve from time zero to infinity of 186 +/- 16 micrograms.hr per milliliter. Renal clearance of fluconazole was 65% +/- 5% of total clearance and demonstrated the predominantly renal excretion of this drug. We suggest that the shorter serum half-life and the higher frequency of aminotransferase elevations in comparison with those of adults warrant careful investigation of fluconazole in controlled clinical trials.

Abstract

A parent education booklet describing Pneumocystis carinii pneumonia (PCP) was prepared by the Pediatric Branch of the National Cancer Institute. In addition to information about prophylaxis and treatment of PCP, the booklet discusses overall care of children infected with human immunodeficiency virus.

Abstract

Aerosolized pentamidine has been recommended as an alternative mode of antipneumocystis prophylaxis in human immunodeficiency virus-infected children with trimethoprim-sulfamethoxazole intolerance. However, there have been no definitive data concerning the most appropriate dose and the tolerance of aerosolized pentamidine in children. In the present study, we assessed the tolerance of aerosolized pentamidine in older children using a regimen similar to the one recommended in adults. A 300-mg dose of pentamidine was administered to our human immunodeficiency virus-infected patients monthly using the Respirgard II nebulizer. Patients were assessed for their heart rate, respiratory rate, breath sounds and oxygen saturations during and after pentamidine aerosolization. During a 21-month period (August, 1989, to May, 1991), 22 patients (mean age, 9.8 +/- 0.6 years; range, 3 to 15 years) received a total of 185 treatments. Patients complained of either a bitter taste (16 of 22) or developed short periods of coughing (15 of 22) during the aerosol. Five patients developed reversible bronchospasm requiring bronchodilators; no patients developed oxygen desaturation. None of the patients developed Pneumocystis carinii pneumonia during the limited protocol follow-up (mean, 9.8 months). Thus aerosolized pentamidine for antipneumocystis prophylaxis is well-tolerated in older children. However, more comprehensive investigations of efficacy are indicated.

Abstract

We reviewed all 155 episodes of central venous catheter-associated fungemia among inpatients at the National Cancer Institute during a 10-year period. Candida species accounted for 98% of episodes. Fungemia was documented by culture of blood drawn through catheters in 50% of cases and by culture of both catheter-drawn and peripheral blood in 39%; mortality and the rate of dissemination were similar for these two groups. Four management strategies were used: catheter removal, antifungal therapy (with amphotericin B), both, or neither; indications for the use of both modes of treatment included fever, neutropenia, long-term indwelling catheterization, positive cultures of both catheter-drawn and peripheral blood, isolation of Candida tropicalis, and fungal isolation from two or more blood cultures. Disseminated fungal infection was documented in 82% of cases with these features but also in 35% of the less severe cases treated only with catheter removal. In addition, nine (82%) of 11 cases managed only with antifungal therapy had a negative outcome (either death from disseminated infection or the recurrence of fevers and/or fungemia), a finding suggesting that intravascular catheters should be removed in fungemia. Virtually all cases of catheter-associated fungemia in patients with cancer are clinically significant and require prompt therapy with amphotericin B.

Abstract

Ganciclovir and foscarnet are both effective for cytomegalovirus retinitis in patients with acquired immunodeficiency syndrome, but the benefits of either agent given alone are limited. A child infected with human immunodeficiency virus who had cytomegalovirus retinitis that progressed despite treatment with either agent alone received the combination of ganciclovir and foscarnet. This treatment resulted in a sustained clinical response.

Abstract

Disseminated candidiasis is the most common life-threatening invasive fungal infection in granulocytopenic patients. A review of recent approaches to pre-clinical laboratory investigation of promising antifungal compounds, which may have potential utility in granulocytopenic patients is presented. A particularly useful strategy is the study of persistently granulocytopenic rabbit models of acute, subacute, and chronic forms of disseminated candidiasis. When the antifungal triazoles (fluconazole, itraconazole, and SCH 39304 [SCH 42427]) were each evaluated for use as preventive, early treatment, or delayed treatment in the different models, the triazoles were consistently more active when used for preventive and early treatment than for delayed treatment. These triazoles were as active as amphotericin B plus flucytosine (AB + FC) when used for early treatment but were less active than AB + FC when used for delayed treatment. Several lipid formulations of amphotericin B demonstrate reduced nephrotoxicity at higher safely achievable dosages in comparison to those of deoxycholate amphotericin B in several models of disseminated candidiasis. When administered to follow non-linear saturable Michaelis-Menten-type plasma pharmacokinetics, the antifungal activity of the echinocandin compound cilofungin was significantly augmented. Thoughtfully designed and carefully conducted laboratory investigations in appropriate animal models of disseminated candidiasis can provide a scientific foundation and guide for development of clinical protocols investigating new approaches to prevention and treatment of invasive candidiasis in granulocytopenic patients.

Abstract

To assess the safety and antiretroviral activity of 2',3'-dideoxyinosine, we enrolled 43 children with symptomatic (Centers for Disease Control class P-2) human immunodeficiency virus infection in a Phase I-II study and monitored them prospectively for the development of ocular complications secondary to HIV infection or drug toxicity. Follow-up ranged from 12 to 103 weeks with a median follow-up of 71 weeks. Three of 43 children (7.0%) developed peripheral atrophy of the retinal pigment epithelium during treatment with 2',3'-dideoxyinosine. The two children with the most severe retinal atrophy were enrolled in the study at the highest dosage studied (540 mg/m2/day). In contrast to findings in children, no retinal atrophy in HIV-infected adults treated with 2',3'-dideoxyinosine has been evident to date.

Abstract

The pharmacokinetics of intravenous and oral 2',3'-dideoxyinosine (ddI) and the relationships between pharmacokinetic parameters and measures of response were studied in 48 human immunodeficiency virus-infected children. Disappearance of ddI from plasma after the intravenous dose was rapid and biexponential, with half-lives of 12 min and 1.0 h and a total clearance of 510 +/- 180 ml/min/m2. After oral administration, ddI absorption was limited and variable (mean bioavailability, 19% +/- 17%). A plasma ddI concentration-response relationship was observed for both decline in viral p24 antigen levels and improvement in intelligence quotient score. A limited sampling model was developed that accurately predicts the area under the ddI plasma concentration-time curve from one to three plasma samples. Although this pharmacokinetic study was done in children, the results also have relevance to adults and suggest that individualization of dose and schedule through therapeutic drug monitoring may be necessary to achieve optimal response.

Abstract

Patterns of infection were studied in 150 patients with aplastic anemia who were admitted to the Clinical Hematology Branch, National Institutes of Health, between January 1978 and December 1989 for immunosuppressive therapy. Sixty percent of the patients were males, 71% were white, their mean age was 33.6 years (median, 27.5; range, 1-75), and 83% had severe aplastic anemia. One hundred three patients developed 1 or more febrile episodes during the study period. The risk factors for developing a febrile episode included a low Absolute Neutrophil Count (ANC) and Absolute Monocyte Count (AMC) at admission and the presence of an indwelling central venous catheter (Hickman-Broviack or Port-A-Cath). A total of 289 febrile events were studied, including unexplained fever (FUO) in 89 (31%), microbiologically documented infection (MBDI) in 137 (47%), and clinically documented infection (CDI) in 63 patients (22%). Compared to documented infections (MBDI) or CDI), FUO events were associated with a higher frequency of rigors, signs and symptoms of serum sickness, and treatment regimens known to cause fevers. None of the FUO events had a fatal outcome, even if the antibiotic therapy was discontinued before day 7. Among CDI events, bacteria were the most commonly defined etiologic agent (67%), followed by fungi (23%), viruses (7%), and parasites (3%). The patterns of bacterial infections in patients with aplastic anemia were similar to those observed in patients with cancer-related neutropenia. Twenty-one patients (15%) developed invasive fungal infections (aspergillus, 11; candida, 7; and both, 3), which were fatal in 19 (90%). Fungal infections accounted for 30% of the secondary infectious events and for 55% of fatal infectious events. The only identifiable risk factors for developing a fungal infection were the degree of neutropenia and monocytopenia at initial admission or final evaluation. Invasive pulmonary aspergillosis developed despite empirical amphotericin B therapy and was associated with a high incidence of fatal pulmonary hemorrhage (10 of 13 patients [77%]). Infection was responsible for 36 (62%) of the deaths observed during the study period and hemorrhage alone for 4 (7%). However, 20 of the patients who died of infection had concomitant hemorrhage. No significant drop in ANC, AMC, or platelet count could be demonstrated during a fatal infectious event as compared to a nonfatal infectious event. Invasive fungal infections, predominantly with aspergillus and candida, emerged in our study as the major causes of mortality in patients with aplastic anemia. Without bone marrow recovery the prognosis associated with invasive mycoses was grave.

Abstract

When radiolabeled RNA was used for in situ hybridization, human immunodeficiency virus type 1 (HIV-1) RNA was found in high concentrations in germinal centers of lymphoid tissues from patients with HIV-1 infection. Most of the signal from hybridized probe was independent of specific cells, being found in the extracellular space of germinal centers in all lymphoid tissues examined from adult patients with Centers for Disease Control (CDC) class II and III disease or pediatric patients with CDC class P-2A disease. Lymphoid tissues from adult patients with CDC class IV infections or pediatric patients with CDC class P-2D disease (including autopsy material) lacked intact germinal centers, and HIV-1 RNA was then found only in rare, isolated cells, with some tissues having no detectable HIV-1 RNA. Thus, in the early stages of HIV infection, germinal centers serve as important reservoirs of free virus in the interstitial spaces, and this reservoir disappears as the germinal centers involute with advancing disease.

Abstract

We conducted a retrospective study to analyze the impact of central venous catheters (CVCs) and antiretroviral therapy on the frequency and the patterns of bacterial infections in children infected with human immunodeficiency virus during a 3-year period. Among 204 bacterial infections other than otitis media reviewed, soft tissue infection (n = 69), bacteremia (n = 57), pneumonia (n = 27) and sinusitis (n = 27) were encountered most frequently. Catheter-related staphylococcal infection was the most common infection in children with CVCs, particularly in those who were less than 6 years old. In children without CVCs, Streptococcus pneumoniae was the most frequent organism. Younger children had more CVC-related infections whereas children with lower CD4 counts had more CVC-related and CVC-unrelated infections. A lower frequency of CVC-unrelated infections was detected in patients who received antiretroviral therapy, especially those receiving a continuous infusion of zidovudine. These data suggest that increased frequency and altered patterns of bacterial infections are associated with the use of CVCs in these patients, but antiretroviral therapy may reduce the frequency of CVC-unrelated infections.

LYMPHOID ORGANS FUNCTION AS MAJOR RESERVOIRS FOR HUMAN-IMMUNODEFICIENCY-VIRUSPROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICAPantaleo, G., Graziosi, C., Butini, L., Pizzo, P. A., Schnittman, S. M., Kotler, D. P., Fauci, A. S.1991; 88 (21): 9838-9842

Abstract

The total number of human immunodeficiency virus type 1 (HIV-1)-infected circulating CD4+ T lymphocytes is considered to be a reflection of the HIV burden at any given time during the course of HIV infection. However, the low frequency of HIV-infected circulating CD4+ T lymphocytes and the low level or absence of plasma viremia in the early stages of infection do not correlate with the progressive immune dysfunction characteristic of HIV infection. In this study, we have determined whether HIV-infected circulating CD4+ T lymphocytes are a correct reflection of the total pool of HIV-infected CD4+ T cells (i.e., HIV burden). To this end, HIV burden has been comparatively analyzed in peripheral blood and lymphoid tissues (lymph nodes, adenoids, and tonsils) from the same patients. The presence of HIV-1 DNA in mononuclear cells isolated simultaneously from peripheral blood and lymphoid tissues of the same patients was determined by polymerase chain reaction amplification. We found that the frequency of HIV-1-infected cells in unfractionated or sorted CD4+ cell populations isolated from lymphoid tissues was significantly higher (0.5-1 log10 unit) than the frequency in peripheral blood. Comparable results were obtained in five HIV seropositive patients in the early stages of disease and in one patient with AIDS. These results demonstrate that a heavy viral load does reside in the lymphoid organs, indicating that they may function as major reservoirs for HIV. In addition, the finding of a heavy viral load in the lymphoid organs of patients in the early stages of disease may explain the progressive depletion of CD4+ T lymphocytes and the immune dysfunction associated with the early stages of HIV infection.

THE EVOLVING USE OF BIOLOGICALS IN THE TREATMENT AND PREVENTION OF INFECTIOUS-DISEASESREVIEWS OF INFECTIOUS DISEASESPizzo, P. A.1991; 13 (5): 971-972

Abstract

Although the studies presented in this symposium illustrate the benefits of biologicals in treating patients whose immune systems have been compromised by congenital or acquired immunodeficiencies, it is likely that in the future these agents will also play a role in the management of immunocompetent persons suffering from complications of infection. The insights resulting from the work discussed here provide a strong basis for making that possibility a reality.

Abstract

Cilofungin (LY-121019) is a fungicidal cell wall-active 1,3-beta-glucan synthetase inhibitor with a short plasma half-life and saturable nonlinear plasma pharmacokinetics. To optimize the in vivo efficacy of this compound, we studied the effects of its linear and nonlinear pharmacokinetics during continuous versus intermittent intravenous infusion of cilofungin in the treatment of experimental disseminated candidiasis in persistently granulocytopenic rabbits. Six groups of rabbits were studied, untreated controls (n = 32) and five cilofungin dosage regimen groups consisting of the following: 25 mg/kg of body weight intravenously twice daily (VLoINT) (n = 9); 50 mg/kg twice daily (LoINT) (n = 9); 90 mg/kg twice daily (HiINT) (n = 11); 5 mg/kg/h for 18 h/day (LoCI) (n = 7); and 10 mg/kg/h for 18 h/day (HiCI) (n = 7). All regimens achieved plasma concentrations exceeding the MIC for Candida albicans (0.25 microgram/ml). In vitro timed kill assays found that the fungicidal activity and rate of kill by cilofungin above the MIC for C. albicans was concentration dependent. At the lower dosage regimens (VLoINT, LoINT, and LoCI), cilofungin followed linear plasma pharmacokinetics, whereas at higher doses (HiCI and HiINT), nonlinear kinetics consistent with a saturated elimination pathway(s) were observed. Only HiCI and HiINT produced a 10(3)- to 10(4)-fold reduction in CFU per gram in candidiasis of the brain (P less than or equal to 0.001). HiCI and HiINT also significantly reduced infection in the choroid (P less than or equal to 0.05). All regimens, except VLoInt, significantly (P less than or equal to 0.01) reduced tissue infections in lung, liver, spleen, and kidney. However, only the regimens with nonlinear saturation kinetics (HiCI and HiINT) produced a 10(6) reduction in the spleen and a > 10(5) reduction of C. albicans in the kidney and liver. A simple doubling of the dosage from LoCI to HiCI resulted in tissue concentrations that were 10 times higher and a 10(2)- to 10(4)-fold-greater antifungal effect. There was a direct correlation (r2 = 0.83) between tissue concentrations of cilofungin and antifungal activity. Thus, continuous and intermittent infusion dosage regimens that elicit nonlinear saturation plasma pharmacokinetics of cilofungin were associated with increased antifungal activity against experimental disseminated candidiasis.

Abstract

Late recurrent Candida endocarditis (LRCE) developed on a prosthetic mitral valve 22 months after treatment for primary native mitral valve endocarditis. The LRCE was difficult to diagnose; results of two dimensional echocardiography and repeated blood cultures were negative. Only transesophageal echocardiography revealed a vegetation and only lysis centrifugation blood cultures demonstrated candidemia. Postmortem examination revealed a large Candida vegetation on the prosthetic valve and Candida in the mitral valve ring. This case and a review of the literature indicate that Candida endocarditis treated with amphotericin B and prosthetic valve replacement may recur months after treatment, and that LRCE, which is difficult to diagnose and treat, may be best prevented by lifelong antifungal suppressive therapy.

Abstract

The plasma pharmacokinetics and tissue penetration of Bay R 3783 (BR), a new antifungal triazole, and one of its active metabolites, Bay U 3625 (BU), were studied in rabbits. Plasma levels of BR and BU were determined simultaneously in five rabbits for six days after a single oral dose of 20 or 40 mg/kg BR. For BR, the mean Cmax was 1.9 +/- 0.4 mg/l, the Tmax 2.0 +/- 0.7 h, the AUC alpha 7.5 +/- 1.6 mg.h/l, and the terminal plasma T1/2 2.1 +/- 0.1 h. For BU, the mean Cmax was 0.84 +/- 0.09 mg/l, the Tmax 24 +/- 4 h, the AUC alpha 61.9 +/- 6.5 mg.h/l, and the plasma T1/2 was 48 +/- 3 h. In a multi-dose study, the plasma BR clearance during wash-out gradually diminished, suggesting possible metabolite inhibition of BRs biotransformation. No hepatic or renal toxicity was seen after 28 days of dosing with BR 40 mg/kg/d. Both BR and BU penetrated well into tissues, with tissue drug concentrations over three times higher than in plasma at multiple tissue sites. Persistence of BU in plasma, however, resulted in prolonged, higher tissue levels of BU than of BR. We conclude that BR is converted to a long-lasting active metabolite BU, that persistence of BU in tissue is prolonged, and that these properties may permit BU to contribute significantly to the antifungal activity of BR.

Abstract

Helper T-cell function was evaluated in 34 children infected with human immunodeficiency virus type 1, by assessing interleukin-2 production after stimulation of peripheral blood mononuclear cells with recall antigens (influenza virus, tetanus toxoid), allogeneic HLA, and phytohemagglutinin. In addition, helper T-cell function was correlated retrospectively with the incidence of opportunistic and bacterial infections. Four patterns of helper T-cell function were observed: (1) 7 (21%) of the 34 children responded to all stimuli, (2) 7 (21%) of them responded to alloantigens and phytohemagglutinin but not to recall antigens, (3) 7 (21%) responded to phytohemagglutinin but not to recall antigens or alloantigens, and (4) 13 (37%) did not respond to any of these stimuli. There were no significant differences related to different routes of acquisition among patients. Patients with functional helper T-cell defects had a history of more opportunistic (p = 0.03) and bacterial (p less than 0.001) infections than did patients with intact helper T-cell function. Thus distinct patterns of helper T-cell dysfunction exist in children infected with human immunodeficiency virus type 1 and correlate with higher frequency of infections. Comparisons of in vitro helper T-cell responses to these stimuli may be useful for detecting early functional helper T-cell defects and for monitoring progression of disease.

Abstract

The early diagnosis of invasive fungal infection in granulocytopenic patients remains unreliable. Granulocytopenic patients who are persistently or recurrently febrile despite therapy with appropriate antibacterial agents are at high risk for the development of such infection. Two randomized clinical trials demonstrated that the empiric administration of amphotericin B to persistently or recurrently febrile granulocytopenic patients decreased the frequency, morbidity, and mortality of invasive fungal infection; these effects were especially marked in profoundly granulocytopenic patients who were not receiving antifungal prophylaxis. Current studies continue to indicate that prompt empiric administration of amphotericin B to persistently or recurrently febrile granulocytopenic patients ensures earlier treatment of deep mycoses. The roles of newer antifungal triazole compounds and of liposomal and lipid complexes of amphotericin B in empiric antifungal therapy must be investigated further in thoughtfully designed, randomized clinical trials.

Abstract

Invasive candidiasis is a major nosocomial infection that is difficult to diagnose. Few biochemically defined markers of invasive candidiasis are known. Initial findings suggested that the presence of candida enolase in the blood may be a novel marker for invasive candidiasis.We tested 170 patients at high risk for invasive candidiasis for candida enolase antigenemia. All the patients had cancer and neutropenia. We detected antigen using a double-sandwich liposomal immunoassay for candida enolase in serially collected serum samples. Invasive candidiasis was proved by finding candida species in deep nonmucosal tissue, blood cultures, or both. Antigen testing was performed with the investigator blinded to tissue or culture diagnosis.Among 24 patients with proved invasive candidiasis, 149 serum samples were tested for enolase antigenemia; 80 were positive and 69 negative (sensitivity per sample, 54 percent). Multiple sampling improved the detection of antigenemia, which was found in 11 of 13 proved cases of deep tissue infection (85 percent) and in 7 of 11 proved cases of fungemia (64 percent). Specificity was 96 percent as measured against control groups including patients with mucosal colonization, bacteremia, and other deep mycoses. Antigenemia was detected in the absence of fungemia in 5 cases of deep tissue candidiasis, but was not detected in 6 cases of fungemia alone.Candida enolase antigenemia is a novel marker for invasive candidiasis. It may be a useful indicator of deep infection in patients with cancer and neutropenia and may complement the diagnostic usefulness of blood cultures.

Abstract

We compared high-dose ketoconazole (800 mg/kg per day, orally) with amphotericin B (0.5 mg/kg per day, intravenously) for empirical antifungal therapy in a prospective, randomized study of persistently or recurrently febrile granulocytopenic cancer patients. Among 97 patients eligible for empirical antifungal therapy, 20 (21%) of these patients were ineligible for randomization to ketoconazole treatment because of their inability to tolerate oral medications. Among 72 patients eligible for randomization, 64 were assessable (32 in each arm of the study). Five of six patients with proved fungal infections who were randomized to receive ketoconazole treatment required crossover to amphotericin B treatment because of progressive infection. The conditions of three of these five patients improved after receiving amphotericin B. The frequency of transaminase elevation was higher in those receiving ketoconazole, while the frequency of azotemia was higher in those receiving amphotericin B. Bioavailability of ketoconazole was unpredictable. Amphotericin B remains the drug of choice for empirical antifungal therapy in granulocytopenic patients; whereas, lack of a parenteral formulation, ineffectiveness against proved mycoses, and unreliable bioavailability preclude high-dose ketoconazole from being an appropriate compound for this purpose.

Abstract

The majority of asymptomatic, human immune deficiency virus seropositive (HIV+) individuals exhibit a defect in CD4+ T helper cell (Th) function that is selective for responses to recall antigens, but not to HLA alloantigens. The CD4-dependent Th response to HLA alloantigens (Allo) can be mediated by two distinct Th pathways: self-restricted CD4+ Th that recognize allogeneic determinants processed and presented by autologous or self accessory or antigen-presenting cells (sAC); and allo-restricted, CD4+ Th that recognize allogeneic determinants directly on allogeneic accessory or antigen-presenting cells (aAC). In contrast, the Th response to recall antigens requires CD4+ Th and sAC and is therefore limited to the major histocompatibility complex (MHC) self-restricted pathway. Peripheral blood leukocytes from 56 asymptomatic HIV+ patients that exhibited a selective defect in CD4+ Th function were analyzed to determine whether the Th response to Allo was entirely functional, or whether one of the CD4-mediated components of the Allo Th response was also defective. By depletion of AC and/or CD8+ Th subsets (to analyze CD4+ Th function), we demonstrated that HIV+ patients who were selectively deficient in Th function to recall antigens were also unresponsive to Allo presented by autologous AC (HLA self-restricted Th pathway), but retained Allo Th activity presented by allogeneic AC (allo-restricted CD4+ Th pathway). These findings indicate that the CD4+ Th defect seen in the majority of asymptomatic, HIV+ individuals is not limited to recall antigens, but also extends to the component of the response to HLA alloantigens that involves the self-restricted, CD4+ Th pathway. Thus, the Th defect observed in asymptomatic, HIV+ patients does not involve a CD4+ Th defect per se, but is limited to the HLA self-restricted component of Th function.

Abstract

Leptotrichia buccalis, an anaerobic gram-negative rod, is part of the normal oral flora and has rarely been isolated from clinical material. We describe four patients with neutropenia and progressive malignancy who had symptomatic L. buccalis bacteremia, and we review an additional four cases from the literature. The mean age of the patients was 31 years (range, 7-73 years), with an equal number of males and females. The number of positive blood cultures in each case ranged from one to four (mean, two); these cultures became positive after 48-120 hours (median, 54 hours). All tested isolates were sensitive to the beta-lactam agents, clindamycin, tetracycline, and metronidazole; five of seven were sensitive to chloramphenicol; and not one was sensitive to the aminoglycosides, vancomycin, ciprofloxacin, or erythromycin. Seven patients had one or more possible portals of entry for bacteremia, including mucositis (four patients), mucositis plus esophageal lesions (two), and possible mucositis plus diverticulitis (one). L. buccalis should be considered a potential pathogen in neutropenic patients, especially when breaks in the mucosal breaks in the mucosal barriers are present.

Abstract

Granulocyte colony-stimulating factor (G-CSF) stimulates proliferation of myeloid cells and may be a valuable adjunct in prevention and treatment of neutropenia-associated infections. Neutrophil (PMNL) phagocytic and microbicidal functions against Staphylococcus aureus and Candida albicans blastoconidia were therefore evaluated. Bacterial phagocytosis and bactericidal activity were significantly enhanced by approximately 50%-70% after preincubation of normal PMNL with G-CSF in concentrations of 1000-4000 units/ml for 10 min at 37 degrees C. G-CSF in similar concentrations enhanced the defective bactericidal activity of PMNL from HIV-1-infected patients by approximately 70%-150% and reached the baseline control PMNL killing. However, G-CSF enhanced neither phagocytosis nor fungicidal activity of normal PMNL against C. albicans blastoconidia. These data demonstrate that G-CSF enhances the antibacterial but not the antifungal activities of human PMNL in vitro and also improves the defective PMNL bactericidal activity of HIV-1-infected patients.

Abstract

We studied serum concentrations of IgG subclasses in 47 human immunodeficiency virus 1-infected (17 asymptomatic and 30 symptomatic) children. Thirty-nine of 47 (83%) had an abnormality of at least 1 subclass. Sixteen had only elevated IgG1, 6 had only elevated IgG3 and 12 had elevated IgG1 and IgG3 concentrations. IgG2, IgG4 and combined IgG2-IgG4 deficiency was found in 3, 4 and 4 patients, respectively. IgG2 concentrations did not differ between patients with (n = 23) or without (n = 24) bacterial infections. Additionally the number of bacterial infections was similar between the patients with normal or low IgG2 and/or low IgG4. These data indicate that IgG subclass abnormalities are found in most children with human immunodeficiency virus 1 infection, but quantitative deficiencies of specific subclasses do not appear to explain the high frequency of bacterial infections occurring in these patients.

Abstract

2',3'-Dideoxyinosine (ddl) is a dideoxynucleoside with potent activity in vitro against the human immunodeficiency virus (HIV). In initial clinical trials in adults, ddl showed evidence of antiretroviral activity with little hematologic toxicity.We conducted a phase I-II study in 43 children with symptomatic (CDC class P-2) HIV infection. Of these children, 16 (median age, 10 years) had previously received zidovudine, and 27 (median age, 2.6 years) had not. ddl was administered orally in three divided doses totalling 60, 120, 180, 360, or 540 mg per square meter of body-surface area per day for 24 weeks. Eight of the 43 patients did not complete 24 weeks of ddl: 6 died, 1 was withdrawn because of progressive disease, and the other because of toxicity.After oral administration, ddl was rapidly absorbed, although its bioavailability varied greatly among patients. Pancreatitis developed in two children, one receiving ddl at each of the two highest doses. The median CD4 cell count in 38 patients with paired counts increased from 0.218 x 10(9) per liter (218 per cubic millimeter) at base line to 0.327 x 10(9) per liter (327 per cubic millimeter) after 20 to 24 weeks (P = 0.001). Those with CD4 cell counts above 0.1 x 10(9) per liter (100 per cubic millimeter) at base line were significantly more likely to improve in this respect. The median levels of p24 antigen (in 27 patients with detectable levels at entry) declined from 272 pg per milliliter at base line to 77 pg per milliliter at 20 to 24 weeks (P = 0.005). The plasma concentration of ddl correlated significantly with both the degree of decline in the p24 antigen and the degree of improvement in IQ score. Improvement in clinical and immunologic measures occurred in both the previously untreated patients and in those who had been treated with zidovudine.Dideoxyinosine was well tolerated and showed promising antiretroviral activity in HIV-infected children. The correlation between the clinical response and the plasma concentration of ddl indicates that bioavailability is an important consideration in the use of ddl to treat HIV infection and that individualized pharmacokinetic monitoring and dose adjustment may be important for optimal activity.

Abstract

Patients with disseminated infections caused by Trichosporon beigelii have a circulating antigen that cross-reacts with the polysaccharide capsule of Cryptococcus neoformans. We studied the localization of this antigen by immunoelectron microscopy in a rabbit model of experimental disseminated trichosporonosis. Deparaffinized lung sections were examined by using a murine monoclonal anti-cryptococcal polysaccharide antibody and colloidal gold particles coated with goat antibody to murine immunoglobulin G. Antigen that cross-reacted with the monoclonal antibody was observed in the T. beigelii cell wall and in a fibrillar matrix extending from the cell wall.

Abstract

Transfusion of peripheral blood monocytes may be of benefit as adjuvant treatment of leukopenic patients with serious infections. To study the feasibility of this approach, a large-scale monocyte separation procedure employing leukapheresis, density gradient centrifugation, and counterflow centrifugal elutriation was established. By processing 5 to 6 liters of normal donor blood, it was possible to obtain a mean of 1.1 x 10(9) (range: 0.5-1.7 x 10(9) cells) of mononuclear cells, of which 89% (range: 82-94%) were monocytes by Wright's stain morphology. When the elutriation was performed in XVIVO-10, a commercially available, serum-free medium developed for adoptive immunotherapy, spontaneous secretion of superoxide by the monocytes was significantly higher than for monocytes elutriated in Hanks' balanced salt solution without calcium and magnesium or non-elutriated peripheral blood mononuclear cells. This stimulated state of the monocytes was observed both immediately after elutriation and after overnight storage at 4 degrees C, and it was not affected by the type of storage vessel used. Overnight storage of the monocytes at 37 degrees C resulted in a reversal of the stimulated state of the cells. Monocytes elutriated in XVIVO-10 and kept overnight at 4 degrees C released high amounts of arachidonic acid. A subsequent decrease in this release was seen after additional storage at 37 degrees C for 18 hours. These observations demonstrate that separation and storage variables have important effects on the state of stimulation of monocytes. Further investigations of such variables may suggest improved procedures for preparation and storage of these cells, as well as possible ways to stimulate monocytes prior to transfusion.

The current status of antiretroviral agents in the treatment of HIV infection in children: An update from teh Pediatric Branch, National Cancer Institute.Pediatric AIDS and HIV infection: Fetus to AdoescentMueller BU, Pizzo PA1991; 2: 346-52

Abstract

The ventricular area at the level of the foramen of Monro was measured from axial x-ray computed tomography (CT) scans obtained prior to and 6 months after the initiation of continuous infusion of zidovudine (ZDV) in eight children with human immunodeficiency virus-induced encephalopathy. Evidence of moderate to severe central atrophy was present on initial CT scans (p less than 0.05). Ventricular area and ventricular brain area ratio (VBR) decreased after ZDV therapy in seven of eight children (mean decrease of 21.5 and 20%, respectively, p less than 0.05). The degree of decrease in VBR correlated with reductions in cerebrospinal fluid (CSF) protein concentration (r = 0.93, p less than 0.01), but not lymphocyte T4 or T8 counts. Intelligence quotients (IQs) improved in all seven children tested (mean improvement of 17.7%, p less than 0.01) and correlated significantly with reductions in CSF protein concentration (r = -0.85, p = 0.003). The magnitude of IQ changes was not significantly correlated with the magnitude of changes in ventricular area. We conclude that the cognitive improvement of HIV encephalopathy seen after 6 months of continuous infusion of ZDV is accompanied by reduction in brain atrophy and decreased CSF protein, suggesting an ameliorating effect of ZDV on the pathogenesis of AIDS encephalopathy in children.

Abstract

Neuropsychologic function was assessed in 13 children with symptomatic human immunodeficiency virus disease (Centers for Disease Control Class P2), ranging in age from 14 months to 12 years. Before the initiation of treatment, eight patients were classified as having encephalopathy. Psychologic tests were administered both before and after 6 and 12 months of continuous-infusion azidothymidine (AZT; zidovudine) treatment. After 6 months of treatment a significant increase of 15.5 (+/- 3.3) IQ points was demonstrated in general cognitive functioning (p less than 0.001). Follow-up for 10 of these patients indicated that after 12 months of AZT therapy, they had maintained their gains in IQ points. Improvements in adaptive behavior after 6 months of therapy, assessed with a standardized interview, paralleled the findings on the IQ data. No significant differences in the amount of change was observed for the different subgroups. The magnitude of these improvements could not be explained by practice effects, environmental changes, or general improvement in physical state. We conclude that neuropsychologic function was significantly improved with continuous infusion AZT treatment.

Abstract

We observed considerable variability in colony and microscopic morphology among isolates of Trichosporon beigelii. Deeply invasive clinical isolates showed four distinct morphotypes and spontaneous conversions among certain morphotypes and grew well at 37 degrees C. In contrast, superficial clinical and environmental isolates did not demonstrate such morphotypes or conversions, and most grew poorly at 37 degrees C. Thus, the morphologic and physiologic features of invasive clinical isolates of T. beigelii follow certain patterns distinct from those of superficial clinical and environmental isolates.

Abstract

By the mid 1990s the number of newly diagnosed children with HIV infections in the US may rival the 6,500 children diagnosed with cancer each year. But recent developments in therapy for the child with AIDS offer some hope. A pediatric trial at the NCI used a continuous infusion of azidothymidine in order to achieve the desired blood and cerebrospinal fluid levels. Objective and subjective evidence of response to therapy was noted in all patients who presented with neurodevelopmental deficit. Increases in appetite and weight gain and reductions in lymphadenopathy and hepatosplenomegaly, and increases in CD4 count similar to those observed in adults were apparent. Promising preliminary results have also been seen in trials of dideoxycytidine, dideoxyinosine, and recombinant CD4.

Abstract

To determine whether a short course of 2',3'-dideoxycytidine (ddC) could provide safe antiretroviral activity in children with symptomatic human immunodeficiency virus infection and whether it could be used with azidothymidine (AZT, zidovudine). The goal was to maintain uninterrupted antiretroviral therapy while sparing AZT-related myelosuppression and ddC-related neuropathy.In a pilot study, we evaluated four dosage levels of ddC--0.015, 0.02, 0.03, and 0.04 mg/kg, given orally every 6 hours--in 15 children between 6 months and 13 years of age with Centers for Disease Control P2 (i.e., symptomatic) human immunodeficiency virus infection. Thirteen patients had not had any prior antiretroviral therapy; two patients had received and benefited from AZT, but dose-limiting neutropenia had developed. At each dosage level, ddC was given for 8 consecutive weeks and then stopped. After a 30-day rest, a schedule of ddC for 1 week was followed by 3 weeks of AZT therapy (180 mg/m2 every 6 hours); this alternating schedule was repeated for as long as tolerated. Age-appropriate psychometric testing was performed before the start of ddC therapy and after 8 weeks.During the 8 weeks of therapy with ddC alone, no neutropenia or anemia was observed; 6 of 9 patients had decreases in p24 antigen levels, and 8 of 15 had an increased CD4 cell count. At the 0.04 mg/kg level, a rash developed in three patients; mild mouth sores developed in 9 of 15 patients. On the alternating ddC/AZT schedule, no neuropathy was observed.2',3'-Dideoxycytidine has antiretroviral activity in some children and appears to be safe for short intervals. Longer courses of ddC at lower dosage levels, and schedules integrating ddC into combination regimens, deserve to be explored.

Abstract

We studied the plasma pharmacokinetics and tissue penetration of cilofungin (LY121019), a new echinocandin antifungal compound, by intermittent and continuous infusion in rabbits. Following a single intravenous dose of 50 mg/kg of body weight, the maximum concentration in plasma was 297 +/- 39 micrograms/ml, the area under the curve was 30.1 +/- 6.7 micrograms.h/ml, clearance was 30 +/- 10 ml/min/kg, volume of distribution was 0.85 +/- 0.23 liters/kg, half-life in distribution phase was 3.7 +/- 0.2 min (first 12 min postdose), and half-life in elimination phase was 12.9 +/- 0.7 min. When rabbits received cilofungin by continuous infusion (CI) at 10 mg/kg/h over 6 days, sustained concentrations in plasma of 290 +/- 56 micrograms/ml were seen, more than 50-fold higher than predicted if kinetics were linear. Similarly, at 5 mg/kg/h, high levels were also obtained. Such elevated levels in plasma would not have been predicted from the pharmacokinetic characteristics of cilofungin given as a single intravenous dose. Further pharmacokinetic study at several rates of CI suggested that cilofungin elimination follows Michaelis-Menten kinetics. Simultaneous cilofungin levels in plasma and tissue were then determined for rabbits receiving six intravenous, intermittent doses (ID) of cilofungin at 15 mg/kg every 4 min and for rabbits receiving CI as described above. After ID, the mean of the ratios of cilofungin levels in tissue to those in plasma were highest for liver and bile but very low for cerebrum and cerebellum. After CI, ratios were as much as 89 times higher than for ID and significantly greater in the brain, choroid, kidney, and bile (P less than 0.05). We conclude that following a single dose of cilofungin, the compound is rapidly cleared via first-order kinetics and does not penetrate into the central nervous system, whereas following CI, cilofungin exhibits nonlinear saturable kinetics, is slowly cleared, and significantly penetrates into central nervous system tissues.

Abstract

Because polymorphonuclear neutrophils are the most important component of host defense against bacteria, we assessed their function in 13 children with asymptomatic and 12 with symptomatic infection with human immunodeficiency virus type 1 (HIV-1), and compared their values with healthy adult control values. The functions assessed were (1) chemotaxis, (2) bacterial phagocytosis, (3) superoxide generation, and (4) bactericidal activity. Chemotaxis of polymorphonuclear neutrophils toward the chemoattractant N-formylmethionyl leucyl phenylalanine (FMLP) was significantly decreased in symptom-free infected children compared with control subjects (p less than 0.0001), but was increased in children with symptomatic infection (p less than 0.025). Bactericidal activity of the neutrophils against Staphylococcus aureus was defective in 8 of 12 children with asymptomatic infection (p = 0.016), and in 8 of 9 children with symptomatic infection (p less than 0.00001). Superoxide generation by polymorphonuclear neutrophils on stimulation with FMLP and phagocytosis of S. aureus were normal. Serum from patients with symptomatic HIV-1 infection was not as efficient in low concentrations as normal serum in the ability to opsonize S. aureus. The in vitro bactericidal defect was partially corrected by granulocyte-macrophage colony-stimulating factor (GM-CSF). The results suggest that both cellular (neutrophils) and humoral defects contribute to the increased incidence of bacterial infections in HIV-1-infected children, and that GM-CSF may improve the defective bactericidal activity of polymorphonuclear neutrophils in these patients.

Abstract

To assess whether neuroendocrine dysfunction is present in children with acquired immunodeficiency syndrome (AIDS) and growth failure, we evaluated the thyroid, adrenal, and growth hormone-insulin-like growth factor I (IGF-1) axes in nine children with AIDS and failure to thrive. Basal thyroid-stimulating hormone, free thyroxine, and triiodothyronine levels were normal in eight of the nine children and indicated primary hypothyroidism in one child; thyroxine levels were elevated in four and normal in five children. Thyroxine-binding globulin levels were elevated in all children. Serial measurements of thyroid-stimulating hormone, made hourly from 2 to 6 pm and from 10 pm to 2 am, revealed a flat diurnal rhythm of thyroid-stimulating hormone in six children, which may indicate early central hypothyroidism, and a normal nocturnal rise in the remaining three children. Basal plasma corticotropin and aldosterone levels were normal in all children, plasma renin levels were normal in three and elevated in six children, and cortisol levels were normal or elevated in all children. Corticotropin-stimulated cortisol levels exceeded 500 nmol/L (18 micrograms/dl) in all children except one, who was receiving treatment with ketoconazole. Thus adrenocortical function appeared to be grossly intact. The peak growth hormone responses to provocative testing was normal (greater than 7 ng/ml) in eight children and low in one child. The plasma level of insulin-like growth factor I was normal in eight of the nine children and low in one child. We conclude that growth failure in children with AIDS does not usually result from a recognized endocrine cause and that adrenal function is usually normal. However, endocrine deficiency may contribute to morbidity in some children with AIDS.

Abstract

Dideoxynucleosides (zidovudine[AZT], dideoxycytidine[ddC], and dideoxyinosine[ddI]) are promising new agents for the management of human immunodeficiency virus type 1 (HIV-1) infections. In light of recent data demonstrating defects in the polymorphonuclear leukocyte (PMN) bactericidal activity of HIV-1-infected patients and since many chemotherapeutic agents affect PMN function, we examined their effects on the function of PMNs from both healthy and HIV-1-infected individuals in vitro. AZT (0.1 to 25 microM), ddC (0.01 to 1 microM), and ddI (0.2 to 50 microM) had no effect on viability, chemotaxis to N-fromylmethionyl leucyl phenylalanine, phagocytosis of Candida albicans or Staphylococcus aureus, or superoxide production following stimulation by N-formylmethionyl leucyl phenylalanine. Killing of C. albicans was not affected by AZT but was enhanced by 0.1 and 1 microM ddc (a 1 microM, killing was 26.0 +/- 2.02% compared with 17.0 +/- 0.73% for controls: P = 0.006) and 0.2 to 50 microM ddI (at 10 microM, killing was 25.0 +/- 0.68% compared with 17.8 +/- 0.91% for controls; P = 0.002). Killing of S. aureus was unchanged by AZT and ddC but was significantly enhanced by ddI at 0.2 to 20 microM (at 2 microM, killing was 71.2 +/- 5.57% compared with 51.4 +/- 6.29% for controls; P = 0.0045). In addition, the preexisting defective bactericidal capacity of PMNs from HIV-1-infected patients was enhanced by ddI (P less than 0.025). Potential enhancement by these dideoxynucleosides of certain PMN functions of HIV-1-infected patients deserves further study.

Abstract

To investigate the potential use of SCH-39304 for the prevention and treatment of disseminated candidiasis in granulocytopenic patients, we studied its in vivo antifungal activity as preventive, early, and late treatments in three models (acute, subacute, and chronic) of disseminated candidiasis in persistently granulocytopenic rabbits. SCH-39304 was an effective as amphotericin B alone and fluconazole alone for the prevention of disseminated candidiasis. SCH-39304 alone and fluconazole alone were as effective as amphotericin B plus flucytosine for early treatment of subacute disseminated candidiasis. When treatment was delayed for 5 days to establish chronic disseminated candidiasis, SCH-39304 was less effective than amphotericin B plus flucytosine. In comparison with different treatment regimens, SCH-39304 was more effective in early and preventive treatment. Thus, SCH-39304 was comparable to treatment control regimens in prevention and early treatment of subacute disseminated candidiasis. SCH-39304 also was most effective in granulocytopenic rabbits with disseminated candidiasis when used for prevention or early treatment.

CONSIDERATIONS FOR THE EVALUATION OF ANTIRETROVIRAL AGENTS IN INFANTS AND CHILDREN INFECTED WITH HUMAN-IMMUNODEFICIENCY-VIRUS - A PERSPECTIVE FROM THE NATIONAL-CANCER-INSTITUTECONF ON THE ADVANCES IN THE MANAGEMENT OF HIV DISEASE : FOCUS ON DIDANOSINE ( DDI )Pizzo, P. A.UNIV CHICAGO PRESS.1990: S561?S569

Abstract

Human immunodeficiency virus (HIV) infection in infants and young children differs in a number of ways from that in adults. In most HIV-infected children the infection is acquired perinatally and the course of infection is more accelerated than in adults. Diseases related to B cell defects and dysgammaglobulinemia (e.g., multiple or recurrent bacterial infections) predominate early in the disease, and children can be symptomatic before their CD4+ count decreases. Lymphoid interstitial pneumonitis occurs frequently and almost exclusively in children, and a number of the opportunistic infections (e.g., cryptococcosis, toxoplasmosis) or malignancies (e.g., Kaposi's sarcoma) occur infrequently in children. A major disease manifestation in the pediatric population is HIV encephalopathy, which results in impairment in neurologic development that can lead to loss or lack of developmental milestones and to diminished intellectual function. The methodology and design of clinical trials for the study of pediatric HIV infection should consider these clinical and laboratory manifestations as well as the developmental differences that reflect the disease in infants and young children.

Abstract

Trichosporon beigelii caused fatal disseminated infections that were resistant to amphotericin B in two granulocytopenic patients. In vitro susceptibility studies demonstrated that both index strains of T. beigelii were inhibited but not killed by amphotericin B at achievable concentrations in serum. The minimum lethal concentration for both isolates was greater than or equal to 18 micrograms/ml. Five of seven other isolates were found to have a similar pattern of amphotericin B resistance. The fact that the minimum lethal concentration of T. beigelii was many times greater than its MIC was consistent with a resistance pattern of tolerance. We concluded that T. beigelii may be resistant in vitro to amphotericin B and that this in vitro resistance was correlated with refractory, disseminated trichosporonosis in granulocytopenic patients. T. beigelii should be included in the expanding list of amphotericin B-resistant fungi.

Abstract

Chemotherapy, while undeniably effective in controlling or eradicating a variety of neoplasms, is also accompanied by a number of toxicities. Foremost among these is neutropenia, which places the pediatric cancer patient at risk for serious fungal infections. The fungal organisms most commonly responsible for infection in neutropenic children are Candida, Aspergillus, Mucor, and the Phycomycetes. Common sites of infection include the oral cavity, sinuses, lung, and bloodstream. Recently, candidal infection of the liver was recognized as a growing problem. Diagnosis of deep-seated fungal infections, such as pneumonia and hepatic candidiasis, is extremely difficult, often requiring open-lung or liver biopsy, which a patient's hematologic status may not permit. Because early treatment significantly improves prognosis, empirical antifungal therapy may be indicated in selected patients. Amphotericin B is currently the antifungal agent of choice against most fungal organisms. Antifungal efficacy studies based on animal models of disseminated candidal infection suggest that amphotericin B combined with 5-fluorocytosine (5-FC) is more effective than amphotericin B alone against most deep-seated Candida infections. The investigational drug, fluconazole, appears as effective as amphotericin B plus 5-FC in the prevention and early treatment of disseminated candidiasis, and clinical trials to assess this potentially important role for the new antifungal agent are now being initiated.

Abstract

We characterized the cerebrospinal fluid (CSF) penetration and pharmacokinetics of SCH-39304 in adult rhesus monkeys receiving a single oral dose of SCH-39304 (2.0 mg/kg of body weight). The mean CSF-to-plasma area under the curve ratio was 0.63 (+/- 0.18, standard error of the mean); maximum concentrations were 1.34 micrograms/ml (+/- 0.18) in CSF and 1.96 micrograms/ml (+/- 0.43) in plasma. The mean plasma half-life was 45.7 h (+/- 11), and mean CSF half-life was 38.7 h (+/- 3.5). The mean levels of SCH-39304 at 24 h were 1.48 micrograms/ml (+/- 0.3) in plasma and 0.96 microgram/ml (+/- 0.12) in CSF. We conclude that SCH-39304 effectively penetrates into CSF and achieves concentrations considered active against many opportunistic yeasts and that these concentrations are sustained in CSF for greater than or equal to 24 h.

Treatment of human immunodeficiency virus-infected infants and young children with dideoxynucleosides.American journal of medicinePizzo, P. A.1990; 88 (5B): 16S-19S

Abstract

The safety and activity of several antiretroviral agents are being evaluated for treatment of acquired immunodeficiency syndrome (AIDS) in infants and children. Intermittent oral and intravenous regimens and continuous intravenous infusion of the dideoxynucleoside, 3'-azido-3'-deoxythymidine (zidovudine, AZT), have been shown to be beneficial in improving neuro-developmental function and growth velocity in pediatric patients with AIDS. AZT, however, is limited by the associated development of neutropenia and anemia, which frequently necessitates transfusions. Another dideoxynucleoside, 2',3'-dideoxycytidine (ddC), also shows theoretical promise in the treatment of the pediatric AIDS population. This agent is not associated with the hematologic toxicity induced by AZT but does produce a painful sensory peripheral neuropathy. Sequential therapy with AZT and ddC may limit the toxic effects associated with the use of these drugs individually. Dideoxyinosine and soluble recombinant CD4 are two newer antiretroviral agents that are under investigation for the management of AIDS in infants and children. The activity of recombinant CD4 in preventing the transplacental transmission of human immunodeficiency virus is also being evaluated.

Abstract

To investigate the potential use of fluconazole for prevention and treatment of disseminated candidiasis in granulocytopenic patients, its in vivo antifungal activity was studied in three models of disseminated candidiasis in persistently granulocytopenic rabbits: acute, subacute, and chronic disseminated candidiasis. Fluconazole was compared with the combination of amphotericin B and flucytosine for preventive, early, and late treatment of disseminated candidiasis, depending on the model. Fluconazole was most effective when used for preventive or early treatment of acute and subacute disseminated candidiasis. When compared with the combination of amphotericin B plus flucytosine, fluconazole was similarly effective in early treatment of acute and subacute disseminated candidiasis. When treatment was delayed 6 days after established infection, fluconazole was less active in clearing tissues in comparison with its activity in preventive and early treatment. The combination of amphotericin B plus flucytosine, however, was significantly more active than fluconazole in treatment of chronic disseminated candidiasis in all tissues. In summary, fluconazole was most effective against disseminated candidiasis in persistently granulocytopenic rabbits when used for prevention or early treatment.

Abstract

Thirty-five children with symptomatic human immunodeficiency virus infection were enrolled in a 12-week, three-center phase I study of intravenous and oral zidovudine therapy. At enrollment the children ranged in age from 5 months to 13 years, with a median age of 3 1/2 years. Twenty-one children (60%) had acquired immunodeficiency syndrome and 14 (40%) had the related complex; 20 children had less than 0.5 10(9) CD4+ lymphocytes per liter (less than 500 cells/mm3) at entry. Zidovudine was administered in one of three escalating dose regimens. One or two months of intravenous treatment with zidovudine every 6 hours was followed by orally administered drug on the same schedule; zidovudine was infused at 80, 120, or 160 mg/m2/dose, and the oral dose was one and one-half times the intravenous dosage. Adverse events were similar to those observed in adults. Neutropenia (absolute neutrophil count less than 0.75 10(9)/L (750 cells/mm3] occurred in nine patients. The median neutrophil count fell from 2.50 10(9)/L at entry to 1.72 10(9)/L at the end of the study. Anemia requiring transfusion occurred in seven 10(9)/L at the end of the study. Anemia requiring transfusion occurred in seven patients; the median hemoglobin level among nontransfused patients decreased from an entry value of 108 to 105 gm/L (10.8 to 10.5 gm/dl). Dosage adjustments were made in 15 patients, in 12 because of anemia or neutropenia. No patients required permanent discontinuation of zidovudine because of toxic effects. Positive effects included a faster-than-anticipated rate of weight gain, decreased hepatosplenomegaly, and lowering of the total IgG and IgM concentrations toward more normal values. Zidovudine appears to be safe and to have manageable toxic effects in children.

CURRENT ISSUES IN THE ANTIBIOTIC PRIMARY MANAGEMENT OF THE FEBRILE NEUTROPENIC CANCER-PATIENT - A PERSPECTIVE FROM THE NATIONAL-CANCER-INSTITUTEJOURNAL OF HOSPITAL INFECTIONPizzo, P. A.1990; 15: 41-48

Abstract

In summary, the overall approach to the treatment of neutropenic cancer patients is to bridge the neutropenic gap. Empirical therapy serves as an important pillar of support, and a rational programme for modifications of the initial therapy, according to the evolving clinical course of the patient, forms another pillar in bridging this gap (Pizzo & Meyers, 1989). The incorporation of biologicals that might shorten the duration of neutropenia could potentially lead to greater improvements in outcome and greater success for therapy for the febrile neutropenic cancer patient.

Abstract

A paired-ion high-performance liquid chromatographic method was developed to measure concentrations of 2',3'-dideoxyinosine (ddI) in human plasma, urine and cerebrospinal fluid. Samples were prepared using a solid-phase extraction technique which allows for a five-fold concentration of the drug. 2'-Deoxyguanosine was added as an internal standard prior to the extraction. Recoveries for 2'-deoxyguanosine and ddI were 80 +/- 15 and 85 +/- 10%, respectively. Extracted samples were then injected onto a C18 column and eluted isocratically with a mobile phase containing 0.1% of the ion-pairing reagent, heptafluorobutyric acid, and 5% acetonitrile. The retention time was 7.4 min for 2'-deoxyguanosine and 8.4 min for ddI. The lower limit of detection for ddI is 0.1 microM. Using this technique the acid lability of ddI was demonstrated and the plasma concentration versus time profile from a patient receiving the drug was examined.

Abstract

To determine the potential for the use of fluconazole for prevention and treatment of disseminated candidiasis in granulocytopenic patients, we investigated its activity and pharmacokinetics in models of acute, subacute, and chronic forms of disseminated candidiasis in persistently granulocytopenic rabbits. Fluconazole was administered for systemic prophylaxis, early treatment, and delayed treatment. Single-dose and steady-state plasma pharmacokinetics, tissue penetration, and dose-response studies of the investigational compound were studied in subacutely infected granulocytopenic rabbits. Fluconazole was more effective when used for systemic prophylaxis or early treatment of disseminated candidiasis than for delayed treatment. Fluconazole was as effective as amphotericin B plus flucytosine in preventive and early treatment of disseminated candidiasis but was significantly less effective than amphotericin plus flucytosine in the treatment of chronic candidiasis. Dose-response studies demonstrated that the antifungal effect of fluconazole was dose- and time-dependent. Studies of the pharmacokinetics of fluconazole in rabbits demonstrated a long half-life in plasma and a large volume of distribution, properties that correspond to the attainment of high levels of penetration into tissues at multiple organ sites. We conclude that fluconazole is effective for prevention and early treatment of disseminated candidiasis in persistently granulocytopenic rabbits and that the evaluation of its use in preventive or early treatment of disseminated candidiasis in carefully designed clinical trials is warranted.

Abstract

Twenty-four cancer patients with diffuse interstitial pneumonitis (DIP) were randomized to undergo an open lung biopsy (OLB) within 8 hours of presentation (12 patients) or to receive empiric antimicrobial therapy (ET) with trimethoprim-sulfamethoxazole (TMP-SMX) erythromycin for a minimum of 4 days (12 patients). Patients whose condition deteriorated underwent an OLB on day 4. Eight of 12 patients (67%) having OLB survived versus 10 of 12 (83%) receiving ET (P = .64). Morbidity occurred in nine of 12 (75%) having OLB versus eight of 12 (67%) receiving ET (P = 1.0). Concurrently, there were 14 additional cancer patients with DIP who were not randomized (nine refused, three had a coagulopathy contraindicating surgery, two were excluded by primary care physicians) and who were comparable demographically to the randomized group. Two received OLB and 12 ET. Combining the randomized and nonrandomized groups, eight of 14 (57%) having an initial OLB survived versus 18 of 24 (75%) of ET-treated patients (P2 = .19). Results of the OLB were seven Pneumocystis carinii pneumonia (PCP), five nonspecific pneumonitis (NSP), one cytomegalovirus, and one lymphoma. Results of OLB led to discontinuation of antibiotics in three patients. Of the 24 ET patients, eight failed to improve by day 4 and had an OLB. Results were two NSP, two PCP, two cancer, one blastomycosis, and one Candida pneumonia. Complications were seen in 10 of 14 (72%) initial OLB patients versus 14 of 24 (58%) patients on the ET arm (P = .65). When the complication rate between patients receiving only empiric antibiotics was compared with all patients having an OLB (initially or on day 4), the difference was greater in patients undergoing OLB (37% v 72%, respectively) (P2 = .14). ET with TMP-SMX plus erythromycin and broad spectrum antibiotics in granulocytopenic patients appeared to be as successful and potentially less toxic than an OLB in this study. Although the number of patients in this study was small, these data suggest that a trial of empiric antibiotic management may be reasonable in cancer patients presenting with DIP, especially if they are nonneutropenic.

Abstract

Polymorphonuclear leukocytes (PMNs) are an important component of the host defense against fungi. We investigated the influence of five antifungal agents on PMN function and compared them with amphotericin B (AmB). The in vitro effects of AmB, flucytosine, ketoconazole, fluconazole, Sch-39304, and cilofungin (LY121019) on chemotaxis, phagocytosis, oxidative metabolism of PMN as reflected by superoxide anion (O2-) generation, and intracellular killing of Candida albicans blastoconidia were examined. With regard to chemotaxis in response to N-formylmethionyl-leucyl-phenylalanine, as measured by the multiwell chamber method, AmB induced a marked decrease (greater than or equal to 5 micrograms/ml), whereas ketoconazole at 5 micrograms/ml enhance it. Phagocytosis was significantly decreased after pretreatment of PMNs with AmB and Sch-39304 (greater than 5 and 1 to 10 micrograms/ml, respectively). O2- production after stimulation of PMNs with N-formylmethionyl-leucyl-phenyl-alanine was significantly decreased by AmB (greater than 5 micrograms/ml) and enhanced by Sch-39304 (1 to 5 micrograms/ml). In contrast, intracellular killing, as tested by methylene blue staining, was enhanced by ketoconazole (5 micrograms/ml) and Sch-39304 (1 to 5 micrograms/ml). Flucytosine, fluconazole, and cilofungin did not affect PMN function at therapeutic concentrations. The results of this comprehensive study indicate that AmB, flucytosine, cilofungin, and the newer azoles, at safely achievable concentrations, generally do not suppress PMN function at therapeutic enhance selective functions.

Abstract

During a 15-month period, 92 patients undergoing 129 treatment episodes of immunotherapy with interleukin-2 (IL-2) alone or with immune cells underwent insertion of central venous catheters (CVCs) in the Surgery Branch, National Cancer Institute. Before each catheter insertion patients were prospectively randomized into one of three treatment groups; therapy with intravenous (IV) placebo using D5W, IV oxacillin, or change of the catheter to a new site every 72 hours. The mean duration of catheterization was 3.8 +/- 1.1 days. No patient in the oxacillin arm developed catheter-related sepsis, while eight patients in the control arms (five, line change, three, placebo) developed catheter-related sepsis (P2 = .050). Seven episodes of catheter-related sepsis were due to Staphylococcus aureus and one was due to Staphylococcus epidermidis. Catheter colonization was reduced significantly in the oxacillin arm versus control arms (P = .0001). Staphylococcus aureus, Staphylococcus epidermidis, and other coagulase-negative Staphylococci were sensitive to oxacillin in 89%, 60%, and 50% of cultures, respectively. No evidence of bacterial overgrowth, candida colonization, or candidemia was observed in these patients. Thus this trial demonstrates that treatment with prophylactic oxacillin can decrease the incidence of catheter-related sepsis in patients undergoing immunotherapy with interleukin-2 (IL-2). To our knowledge this is the first prospective randomized trial to evaluate the prophylactic use of systemic antibiotics in the prophylaxis of CVC sepsis.

PRACTICAL ISSUES AND CONSIDERATIONS IN THE DESIGN OF CLINICAL-TRIALS FOR HIV-INFECTED INFANTS AND CHILDRENSYMP ON METHODOLOGICAL ISSUES IN AIDS CLINICAL TRIALSPizzo, P. A.LIPPINCOTT-RAVEN PUBL.1990: S61?S63

Abstract

Intraventricular drug administration via the IR is often used in the therapy of leukemic and carcinomatous meningitis. We reviewed our 10-year experience with 32 patients, with IR placed for intraventricular chemotherapy to characterize infectious complications associated with IR. Infectious complications occurred in 9 patients (27.1%). Local cellulitis (S. aureus) occurred at the site of IR in 2 patients. Seven patients (21.8%) had 12 episodes of bacteriologically proven or clinically suspected meningitis, or positive IR CSF cultures without symptoms (4-P. acnes). While patients with local infection may require IR removal, more than half of those with meningitis may be treated with antibiotics alone without IR removal. Patients with positive cultures in the absence of symptoms may require no therapy at all.

Abstract

New fever in a neutropenic patient mandates prompt institution of empirical broad-spectrum antibiotics. Traditional empirical regimens have relied on combinations that include an aminoglycoside. However, certain classes of newer antibiotics (e.g., third-generation cephalosporins, carbapenems, quinolones) include agents with a broad spectrum and high bactericidal activity that may provide therapeutic alternatives to combination regimens. We previously compared empirical monotherapy with ceftazidime to a combination regimen of cephalothin, gentamicin, and carbenicillin and found the regimens comparable with respect to percentage with success (survival without change of initial regimen; 62% vs 67%), success with modification (survival with additional antibiotics; 33% vs 29%) and failure (death; 5% vs 4%). Imipenem has a broader in vitro spectrum of activity than ceftazidime, particularly against gram-positive organisms and anaerobes, raising the possibility of equivalent or even improved efficacy as monotherapy. Accordingly, we are prospectively randomizing febrile, neutropenic patients to either empirical ceftazidime or imipenem therapy. Imipenem appears to be comparable to ceftazidime in this ongoing study but has not resulted in fewer modifications or secondary infections. Studies assessing the role of quinolones in the management of neutropenic patients are under way.

Abstract

We studied the plasma pharmacokinetics and tissue penetration of Sch 39304 (SCH), a new antifungal triazole, in granulocytopenic [G(+)] and nongranulocytopenic [G(-)] rabbits. Five female New Zealand White G(-) rabbits were given a single oral dose of 2 mg of SCH per kg of body weight. Levels in plasma, determined by gas-liquid chromatography-electron capture, were obtained for 6 days. This procedure was repeated 2 weeks later with the same rabbits, which were induced and maintained G(+) with cytosine arabinoside. There were no significant differences between the pharmacokinetic parameters of G(+) and G(-) rabbits. Among all animals studied, the maximum concentration of the drug in plasma was 1.4 +/- 0.11 micrograms/ml at 4 +/- 0.5 h, the half-life was 25 +/- 1.4 h, the volume of distribution at steady state was 3.8 +/- 0.3 liters, and the area under the concentration-time curve was 44 +/- 3.4 micrograms.h/ml. SCH was detectable in plasma up to day 6. Levels of SCH in tissue were studied at steady state in six G(+) and six G(-) rabbits receiving 2 mg of the drug orally per kg per day for experimental disseminated candidiasis. Tissue SCH levels equalled or exceeded those in plasma (at steady state) at all sites examined, and these ratios were similar in both G(+) and G(-) rabbits. Thus, plasma pharmacokinetics of orally administered SCH were similar for G(+) and G(-) rabbits, and SCH achieved high levels of penetration into multiple tissues, including the liver and the central nervous system.

Abstract

In febrile neutropenic patients, most of whom have cancer, immediate, albeit empiric, antibiotic therapy reduces infectious morbidity and mortality. With respect to definitive therapy, it is stressed that isolate patterns are changing, even as new antibiotics are becoming available. Issues such as single-agent versus combination therapy, as well as preventive strategies, are reviewed.

Abstract

The pharmacokinetics of subcutaneous bolus and continuous infusion azidothymidine (AZT) was studied in rhesus monkeys. Three animals received 100 mg/m2 as a bolus injection both intravenously and subcutaneously, with the order of administration randomly determined. Two animals received a continuous subcutaneous infusion of 25 mg/m2 per h for 12 or 24 h. AZT was measured in plasma by a reverse-phase high-pressure liquid chromatographic assay. Following intravenous bolus administration, AZT elimination was rapid, with a mean half-life of 1.2 h and a mean clearance of 318 ml/min per m2 (range, 200 to 441 ml/min per m2). The bolus subcutaneous dose was rapidly (time to peak concentration, 15 to 30 min) and nearly completely (fraction absorbed, 92%) absorbed without evidence of local tissue toxicity. With continuous subcutaneous infusion of AZT, the steady state was attained within 4 h and steady-state concentrations in plasma in the two animals exceeded 3.0 mumol/liter. No local tissue toxicity was observed at the infusion site. The subcutaneous route may be a practical alternative to intravenous administration of AZT and deserves further clinical study.

Abstract

Brain glucose metabolism was evaluated in four patients with acquired immunodeficiency syndrome (AIDS) dementia complex using [18F]fluorodeoxyglucose (FDG) and positron emission tomography (PET) scans at the beginning of therapy with 3'-azido-2',3'-dideoxythymidine (AZT, zidovudine), and later in the course of therapy. In two patients, baseline, large focal cortical abnormalities of glucose utilization were reversed during the course of therapy. In the other two patients, the initial PET study did not reveal pronounced focal alterations, while the post-treatment scans showed markedly increased cortical glucose metabolism. The improved cortical glucose utilization was accompanied in all patients by immunologic and neurologic improvement. PET-FDG studies can detect cortical metabolic abnormalities associated with AIDS dementia complex, and may be used to monitor the metabolic improvement in response to AZT treatment.

Abstract

Zidovudine pharmacokinetics were determined in 16 children with human immunodeficiency virus infection who were being treated intravenously and orally on an intermittent schedule (every 6 hours). The intravenous doses studied were 80 (n = 3), 120 (n = 4), and 160 (n = 5) mg/m2/dose, infused over 1 hour. Fourteen patients were monitored after an oral dose of zidovudine at 120 (n = 2), 180 (n = 7), or 240 (n = 5) mg/m2/dose. Zidovudine was assayed with a reverse-phase high-pressure liquid chromatography method. Zidovudine disappearance after intravenous administration was rapid and biexponential, with half-lives of 14 and 90 minutes and a total clearance of 641 +/- 161 ml/min/m2. The volume of distribution at steady state was 45 +/- 28 L/m2. These pharmacokinetics parameters are very similar to those reported in adults. When administered orally, zidovudine was rapidly absorbed. The fraction of the oral dose that was bioavailable was 0.68 +/- 0.25, so that a 50% increment in the dose, in the conversion from intravenous to oral administration, resulted in plasma zidovudine concentrations after oral dosing that were nearly identical to those achieved with the 1-hour intravenous infusion. However, a dose of 180 mg/m2 given orally every 6 hours maintained plasma zidovudine concentrations in the target range of 1 mumol/L for less than half of the dosing interval. Other schedules, routes of administration, or oral drug formulations may have to be considered if sustained continuous exposure to micromolar zidovudine concentrations is desired.

Abstract

Fluconazole is a new bis-triazole antifungal compound which has in vivo and in vitro activity against Candida spp. and Cryptococcus neoformans and excellent penetration into cerebrospinal fluid. However, little is known about the penetration of fluconazole into tissue sites other than cerebrospinal fluid. We therefore studied by high-pressure liquid chromatography the penetration of fluconazole into nine different tissue sites at times of peak and trough concentrations in plasma in rabbits. Fluconazole penetrated into all tissue sites. Tissue/plasma concentration ratios were greater at time of trough concentrations in plasma than at times of peak concentrations in plasma. The finding that fluconazole penetrated into target organs commonly infected by Candida spp. and C. neoformans further supports the therapeutic potential of fluconazole for disseminated candidiasis or cryptococcosis in immunocompromised hosts.

Abstract

To define the pharmacokinetics of zidovudine (azidothymidine) in children with human immunodeficiency virus infection.Plasma, urine, and cerebrospinal fluid were obtained following a single 80 mg/m2 body surface dose infused over 1 hour (n = 9), and during a continuous infusion of 0.5 (n = 3), 0.9 (n = 8), 1.4 (n = 7), or 1.8 (n = 3) mg/kg body weight per hour.Outpatient clinic and inpatient ward of the Pediatric Branch of the National Cancer Institute.Twenty-one children (seventeen boys) ranging in age from 14 months to 12 years with symptomatic human immunodeficiency virus infection who were being treated on a phase I-II study of continuous intravenous infusion zidovudine.Zidovudine disappearance following bolus administration was rapid and biexponential with half-lives of 9.6 and 92 minutes, and a total clearance of 705 +/- 330 mL/min.m2. Zidovudine remained above 1 mumol/L, the optimal virostatic concentration in vitro, for only 1.5 hours. In contrast, with continuous infusion steady-state plasma zidovudine concentrations (Css) were maintained above 1 mumol/L continuously, even at the lowest infusion rate. At steady state the ratio of cerebrospinal fluid zidovudine concentration to plasma was 24% +/- 9%. Patients who developed severe neutropenia (absolute neutrophil count less than 0.5 X 10(9)/L) on the continuous infusion regimen had significantly higher plasma Css. Six of eight had a Css greater than 3.0 mumol/L.Pharmacokinetic parameters show that continuous infusion is better than an intermittent schedule in maintaining minimal virostatic concentrations of the drug with a lower daily dose.

CONSIDERATIONS FOR THE PREVENTION OF INFECTIOUS COMPLICATIONS IN PATIENTS WITH CANCER2ND CONF ON CONTROVERSIES IN THE MANAGEMENT OF INFECTIOUS COMPLICATIONS OF NEOPLASTIC DISEASESPizzo, P. A.UNIV CHICAGO PRESS.1989: S1551?S1563

Abstract

Methods of preventing the infectious complications that occur in patients undergoing therapy for cancer have been the focus of considerable research. Because infections arise from both the endogenous microbial flora and newly acquired organisms and because the pathogens include bacteria, fungi, viruses, and/or parasites and affect a number of different body sites, it has been difficult to conceive of a single or simple method of controlling these multiple infectious etiologies. The suppression or elimination of the host's own microbial flora by the use of various prophylactic antibiotics and the reduction in the patient's acquisition of new organisms by the use of isolation techniques have received the greatest attention. While a number of these approaches (including total protected isolation, nonabsorbable antibiotics, trimethoprim-sulfamethoxazole, selective decontamination, and most recently the quinolones) have appeared to reduce the incidence of infections, few have stood the test of time. The advantages and disadvantages of each of these methods are reviewed, and newer promising areas for current and future investigation are considered.

EVALUATION OF FEVER IN THE PATIENT WITH CANCERSYMP ON MANAGEMENT OF INFECTIONS IN IMMUNOCOMPROMISED PATIENTSPizzo, P. A.PERGAMON-ELSEVIER SCIENCE LTD.1989: S9?S16

Abstract

During the last decade, the survival of patients with fever and neutropenia has continued to improve. This is largely a reflection of the increasing repertoire of antimicrobial agents available to treat the fevers and infections that arise in this ever-increasing population of patients. Although it would be optimal if therapeutic decisions could always be made based on the microbial isolates and their sensitivity patterns, this is generally not possible in the cancer patient. Fever remains the predominant manifestation of infection, but the underlying microbial etiology is infrequently delineated. In spite of improved diagnostic tests, clinical acumen along with vigilant and repetitive patient assessment remain the cornerstone for evaluation of the cancer patient who becomes febrile. Indeed, strict adherence to simple principles can have a significant impact on improving the chances for survival of cancer patients who develop fever or infection.

Final report of the United States Department of Health and Human Services Secretary's Work Group on Pediatric Human Immunodeficiency Virus, Infection and Disease: Content and Implications.PediatricsNovello AC, Wise PH, Willoughby A, Pizzo PA1989; 84: 547-55

Abstract

To produce concentrations of zidovudine (AZT) in plasma and cerebrospinal fluid that would provide constant inhibition of the replication of human immunodeficiency virus (HIV), we gave AZT by continuous intravenous infusion to 21 children ranging in age from 14 months to 12 years who had acquired HIV infection through transfusions or perinatally. All patients were symptomatic before AZT treatment (Class P2 of the Centers for Disease Control); 13 (62 percent) had evidence of neurodevelopmental abnormalities. The mean CD4/CD8 ratio was 0.18; 11 patients had CD4 counts below 0.2 x 10(9) per liter. We administered AZT at four dose levels: 0.5, 0.9, 1.4, and 1.8 mg per kilogram of body weight per hour. The plasma drug concentrations achieved at the respective dose levels were 1.9 +/- 0.3, 2.8 +/- 1.4, 3.1 +/- 1.1, and 4.5 +/- 1.0 microM. The steady-state cerebrospinal fluid:plasma ratio was 0.24 +/- 0.07. The only evidence of toxicity was bone marrow suppression. Transfusion was required in 14 patients because of low levels of hemoglobin (5 mmol per liter [less than 8 g per deciliter]). Dose-limiting neutropenia (less than 0.5 x 10(9) polymorphonuclear leukocytes per cubic millimeter) occurred in most patients who received doses of 1.4 mg per kilogram per hour or more. Improvement in neurodevelopmental abnormalities occurred in all 13 children who had presented with encephalopathy before treatment. Serial measurements of IQ before therapy and after three and six months of continuous therapy with AZT showed that IQ scores, including those for verbal and performance IQ, rose in these 13 patients and in 5 other children who had no detectable evidence of encephalopathy before treatment. Most patients also had increased appetite and weight, decreased lymphadenopathy and hepatosplenomegaly, decreased immunoglobulin levels, and increased numbers of CD4 cells. In some patients the improvement in the features of encephalopathy occurred despite the absence of immunologic improvement. We conclude that AZT is beneficial in children with symptomatic HIV infection, especially those with encephalopathy (which may be subclinical), and that the optimal continuous intravenous dose of AZT in children is between 0.9 and 1.4 mg per kilogram per hour.

Abstract

Acquired immune deficiency syndrome (AIDS) in children has until recently been under-reported, since the initial Centers for Disease Control definition of AIDS was restrictive. The case definition has now been revised. Most children with AIDS acquired their infection perinatally and have a parent with established AIDS-related complex or AIDS or belong to a high-risk group. Prior to March 1985, children also acquired human immunodeficiency virus from a contaminated blood product transfusion or from factor replacement for hemophilia. In the United States, AIDS in children occurs predominantly in cities with large populations of intravenous drug users. There are a number of differences between the clinical manifestations of human immunodeficiency virus infection in children compared with adults. For example, recurrent bacterial infection is more common in children, perhaps reflecting the abnormal B cell function that occurs relatively early in the disease course. Certain opportunistic infections (e.g., toxoplasmosis, cryptococcal meningitis) are less common in children than adults. Lymphocytic interstitial pneumonia does not occur in adults but is found in 30 to 50 percent of children. On the other hand, Kaposi's sarcoma and other malignancies are less common in children. Treatment has consisted largely of general supportive care in hospital or at home; this is dependent on the availability and utilization of resources and financial support. However, as anti-retroviral therapy becomes available, studies in children have been initiated. It is hoped that in the future it may be possible to prevent the disease; in the meantime, earlier diagnosis and better therapy are important goals.

Abstract

Infectious complications in children with acute leukemias are reviewed as to incidence, predisposing factors, microbiologic etiologies and treatment. Principles of antimicrobiologic therapy are presented for bacterial, fungal, viral, and protozoal infections seen in children with cancer. Prevention of infection is also discussed.

Abstract

Systemic mycoses continue to emerge as life-threatening infections. Considerable progress in treating these infections is being achieved through better application of established available antifungal agents (amphotericin B, flucytosine, miconazole and ketoconazole), and through development of promising investigational agents (fluconazole, itraconazole). Systemic fungal infections, however, continue to present major problems, including clinical resistance, microbiological resistance, emergence of new pathogens, and involvement of more immunocompromised patients. The purpose of this paper, therefore, is to review the recent progress and current problems in treatment of systemic fungal infections.

Abstract

In order to investigate new approaches in diagnosis, prevention and treatment of infectious complicating chemotherapy-induced granulocytopenia, we developed and prospectively evaluated a method of chronic central venous catheterization for the induction, maintenance and support of persistent granulocytopenia in rabbits. The method entails a central venous silastic catheter with a subcutaneous tunnel and a heparin lock device for repeated non-traumatic sampling of blood and administration of medications. During the course of 10 months, 226 rabbits were studied. Mean duration of catheter placement was 27 days, 17 of which were spent in granulocytopenia. Two-way flow was sustained throughout the duration of placement in 205 rabbits (91%) and for 5,845 (95%) of a total 6,163 catheter-days. All but two catheters could be flushed throughout the duration of their placement. Postoperative infectious complications related to catheter insertion developed in less than 1% of the rabbits. This method of chronic catheterization safely provides long-term venous access for studies requiring frequent venous access, including the painless induction, maintenance, and support of chronic granulocytopenia in rabbits.

Abstract

We developed an experimental model of candidiasis in rabbits with prolonged neutropenia. Rabbits were made neutropenic with cytosine arabinoside (Ara-C) administered through an indwelling silastic catheter that had been surgically implanted in the external jugular vein. Neutropenia was sustained with intravenous Ara-C, and bacterial complications were prevented with parenteral ceftazidime plus ampicillin. Candidiasis was established by intravenously administering Candida albicans or Candida tropicalis (1-2 x 10(5) colony-forming units) and resulted in hepatic and splenic lesions that mimicked those associated with hepatosplenic candidiasis in humans. The kidney proved to be the site most refractory to eradication of Candida spp. and offered a target organ for assessing antifungal therapy. We evaluated amphotericin B, 5-flucytosine, ketoconazole, and rifampin, alone and in combination. Although each agent reduced the colony counts of Candida in the liver, spleen, and lung, the combination of amphotericin B and 5-flucytosine was the only regimen effective in eradicating renal candidiasis.

Abstract

The immunocompromised host was first defined around the host abnormalities and consequent infections that were associated with congenitally acquired deficiencies. Although the impact of the deficiency on the affected child was considerable, the numbers of such children remained small. With the advent of immunosuppressive therapy and cytotoxic regimens for the effective treatment of cancers and autoimmune diseases, an increasingly larger number of children became immunocompromised and thus subject to serious infectious complications. More recently a new population of immunocompromised children have emerged, those infected with the human immunodeficiency virus; over the next several years this group of patients threatens to become the predominant group of "immunocompromised hosts" in pediatrics. Regardless of whether the immunodeficiency is a genetically transmitted immunodeficiency or results from cytotoxic therapy or from infection with human immunodeficiency virus, the incidence and pattern of the infections that occur parallel the targets of the immune system that are adversely affected or destroyed. In some cases, this may represent only a single component of the immune system whereas in others, multiple aspects of the immune matrix have been altered or perturbed. Two goals apply to the management of the immunocompromised child: (1) to identify the basis for the immunodeficiency and to develop methods to restore or replenish it; (2) to define the spectrum of infectious complications that can occur in association with the immunocompromised state and to develop regimens to treat or prevent them, at least until the underlying defects can be dealt with in a more definitive manner.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Eight immunocompromised cancer patients with tissue-proved candidiasis underwent serial abdominal ultrasound (US) and computed tomography (CT). At US, four patterns of hepatic and splenic candidiasis were recognized, one of which the authors call a "wheels-within-wheels" pattern. In addition, periportal linear areas of increased attenuation, possibly calcified, were identified at follow-up, nonenhanced CT. Some abscesses were better seen on nonenhanced CT scans, while others became visible only with enhancement. Although lesions not seen at US were often seen at CT, the opposite was also true. In two cases, pathologic proof of candidiasis was established even when all imaging studies were normal. For maximum imaging sensitivity, patients should be studied with US and nonenhanced and enhanced CT. Even when both US and CT scans are negative, if there is a strong clinical suggestion of candidiasis, open biopsy is recommended.

Abstract

Fifty-seven episodes of anorectal infection in 44 patients with malignant diseases primarily leukemia or lymphoma, have been retrospectively reviewed. Seventeen patients died in hospital, but only in seven cases was the anorectal infection a major contributing cause of death. The most important prognostic indicator of outcome was number of days of neutropenia during the infectious episode. Cultures obtained at the time of surgical drainage or by needle aspiration of the wound revealed multiple organisms in 26 of 29 instances, and anaerobic organisms were the commonest isolates. Anorectal infection was controlled in 28 (55%) of 51 treatment courses when antibiotics were the only treatment given. However, if the antibiotic regimen included both an aminoglycoside and an antibiotic with anaerobic coverage, control of infection was observed in 15 (88%) of 17 cases. There were 26 surgical procedures performed, with acceptable morbidity. Infection was controlled in 19 (73%) of 26 cases treated with surgery and antibiotics. The results support managing most of these infections initially with medical treatment, using an antibiotic regimen that includes an aminoglycoside and a specific drug against anaerobes. Surgery is recommended if there is obvious fluctuance, a significant amount of necrotic tissue evident, or progression of the infection locally or continued sepsis after an adequate antibiotic trial.

Abstract

Focal hepatosplenic candidiasis has been recognized with increasing frequency in recent years. We reviewed the cases of eight patients seen between 1982 and 1985, and information on 60 patients whose cases have been reported in the world literature. The characteristics of focal hepatosplenic candidiasis include persistent fever in a neutropenic patient whose leukocyte count is returning to normal, often coupled with abdominal pain; an elevated alkaline phosphatase level; and less commonly, rebound leukocytosis. The characteristic "bull's eye" lesions seen with hepatic ultrasound examination or computed tomography generally are not detectable until neutrophil recovery has occurred. Diagnosis can be established only by biopsy evidence of yeasts or pseudohyphae in the granulomatous lesions. Cultures are frequently negative, however, especially in patients who have been pretreated with antifungal agents. We review the evolving nature of hepatosplenic candidiasis, focusing on diagnosis and treatment.

Abstract

To determine the appropriate role for vancomycin in neutropenic patients with cancer. To review the incidence, types, and outcome of gram-positive infections in a series of neutropenic patients with cancer.Retrospective review.Inpatient units of the Medical and Pediatric Oncology Branches of the National Cancer Institute.Five hundred and fifty consecutive episodes of fever and neutropenia in patients with cancer randomized prospectively on another study to receive either ceftazidime alone or combination antibiotics for initial empirical therapy.Intravenous vancomycin (dosage adjusted by serum levels).Gram-positive organisms were the commonest of the bacterial pathogens isolated (63%). Of the 53 gram-positive organisms accounting for primary infections (isolated at initial presentation), there were 36 staphylococcal isolates (19 coagulase-negative and 17 coagulase-positive), 13 streptococcal isolates (8 non-group D and 5 group D), and 4 polymicrobial isolates. Of the 22 secondary gram-positive infections (occurring after institution of initial antibiotics), there were 10 streptococcal isolates (9 group D and 1 non-group D), 7 staphylococcal isolates (6 coagulase-negative and 1 coagulase-positive), and 5 polymicrobial isolates. Vancomycin was used to treat 26 of the 53 primary infections, but was begun only after knowledge of the isolate in 25. Vancomycin was used to treat 17 of the 22 secondary infections, and begun only after knowledge of the isolate in 14. This approach resulted in no treatment failures for the primary infections, and a single microbiological failure for the secondary infections. There was a tendency towards a greater proportion of secondary gram-positive infections in the monotherapy group compared to the combination therapy group (16 of 282 compared with 6 of 268 respectively, P2 = 0.04 by the chi-squared test); but all were treated successfully.Vancomycin need not be included in routine empirical therapy for febrile neutropenic patients, but should be added when clinical or microbiological data suggest the need.

Abstract

Amphotericin B (AB) is known as an inhibitor of PMN chemotaxis. The chemotaxis of "large granular lymphocytes" (LGL) which are hypothesized to be involved in the antifungal defenses has been only recently investigated. Therefore we have studied the effect of AB on the LGL chemotaxis. LGL are prepared by centrifugation of peripheral blood non adherent cells on a discontinuous gradient of Percoll. They are more susceptible than PMN to the toxicity and chemotactic inhibition induced by colloidal suspension of AB Fungizone i.v. whereas the microparticular suspension has no effect. Deoxycholate (DOC) used for the AB solubilization is responsible at high doses of Fungizone i.v. (1 and 10(-1) mg/ml) of the toxic effect observed. The particular size seems to be also important. Morever at the therapeutic concentrations (2 to 4 X 10(-3) mg/ml) only the chemotaxis of PMN and LGL induced by FMLP is reduced whereas there is a stimulation of the PMN response to zymosan. The differences in the susceptibility of LGL and PMN to AB may explain the immunomodulation induced by this drug.

Abstract

A retrospective review of cecal and appendiceal complications occurring in young patients with acute leukemia since 1969 was performed. The objective of this study was to determine the relative incidence of appendicitis and typhlitis among patients with acute leukemia who had operation or autopsy in this institution as well as to determine the risks of operative intervention. Fifteen patients with these complications were identified among the 400 patients with acute leukemia seen during this time period. Signs and symptoms of an acute abdomen were present despite immunosuppression. The incidence of sepsis at the time of presentation was 53%. Preoperative risk factors identified most frequently were coagulopathy and organ failure resulting from sepsis. Postoperative morbidity (25%) and mortality rates (8%) were related to the development of infectious complications. Appendicitis occurred in eight of the 15 patients studied, whereas typhlitis or its complications was found in seven patients. No preoperative factors could be found to differentiate typhlitis from appendicitis on clinical examination. It is suggested that operation can be safely performed in neutropenic patients who have acute right lower quadrant pain and signs of peritoneal irritation and may be the only effective way of differentiating appendicitis from typhlitis.

Abstract

We retrospectively examined episodes of Bacillus bacteremia at a hospital with a large proportion of immunosuppressed patients. Seventeen episodes in 9.5 years met our case definition: two of two bottles of one blood culture or one of two bottles of two or more separately obtained blood cultures drawn on the same date. During the same period, there were 59 additional episodes in which a single blood culture had only one of two bottles positive for Bacillus species. Only 2 of 59 such episodes resulted in recurrent bacteremia (3%), as compared with 5 of 17 episodes meeting our case definition (29%) (P = 0.004). In four of five episodes complicated by recurrent bacteremia and in which appropriate antibiotics were used, a Hickman-Broviac catheter was in place and was not removed. We suggest that our case definition permits the differentiation of infection from contamination based on outcome and that patients with Bacillus bacteremia have chronic venous catheters removed as well as receive antibiotic treatment.

Abstract

Drug administration via an intraventricular reservoir is useful in the treatment of leukemic and carcinomatous meningitis that occurs in patients who have previously received lumbar intrathecal chemotherapy. The intraventricular route, however, is associated with a higher incidence of infectious complications compared with therapy given by the lumbar route. To characterize the infectious complications associated with such reservoirs, we reviewed the 10-year experience of the Pediatric Branch, National Cancer Institute, National Institutes of Health, and Children's Orthopedic Hospital, Seattle, WA, with 61 patients (49 with leukemia, 8 with lymphoma, 4 with solid tumors) who had intraventricular reservoirs placed for administration of chemotherapy. The reservoirs were in place for a median of 36 weeks and were punctured a median of 29.5 times, Infectious complications occurred in 14 of 61 patients (23%) and Propionibacterium acnes was the most common organism recovered from cultures. Twelve patients (19.7%) had 19 episodes of clinically suspected and microbiologically documented meningitis or of positive intraventricular reservoir cerebrospinal fluid cultures without symptoms which were treated successfully. Local cellulitis occurred at the site of intraventricular reservoir placement in 2 patients (3.3%) and removal of the intraventricular reservoir was necessary for successful management. Nine patients had their intraventricular reservoir removed (5 because of associated infection and 4 because of malfunction unassociated with infection).(ABSTRACT TRUNCATED AT 250 WORDS)

AFTER EMPIRIC THERAPY - WHAT TO DO UNTIL THE GRANULOCYTE COMES BACKREVIEWS OF INFECTIOUS DISEASESPizzo, P. A.1987; 9 (1): 214-219

Abstract

The prompt initiation of empiric broad-spectrum antibiotic therapy when a granulocytopenic patient becomes febrile has become standard practice and has resulted in a significant reduction in the early morbidity and mortality associated with infection. Granulocytopenic patients, however, are at risk for multiple infectious episodes, particularly when the duration of neutropenia is prolonged. Accordingly, the addition of one or more antimicrobial agents to the initial empiric antibiotic regimen is often necessary to deal effectively with these second infections and to help maximize the patient's chance for survival. An organized plan that incorporates modifications of the primary antibiotic regimen (e.g., the addition of another antibiotic or an antifungal agent) into the overall management of the febrile neutropenic patient is important, especially when neutropenia lasts for more than a week.

Abstract

Although usually considered a non-pathogen, Clostridium tertium was isolated from 10 immunosuppressed patients including seven patients with bacteremia. This organism can grow aerobically and can be easily disregarded as a contaminant. It also has a somewhat unusual susceptibility pattern, with significant resistance to the penicillins, cephalosporins, and clindamycin, possibly explaining its emergence in immunocompromised patients already receiving multiple antibiotics.

Abstract

To assess the efficacy of single-agent therapy relative to standard combination antibiotic therapy for the initial management of fever and neutropenia in cancer patients, we conducted a randomized trial comparing ceftazidime alone with a combination of cephalothin, gentamicin, and carbenicillin. Of 550 evaluable episodes of fever and neutropenia, 282 were treated with ceftazidime alone and 268 with the combination. All episodes were evaluated for responses at 72 hours after the start of treatment and at resolution of the neutropenia. Of the patients with unexplained fever who were given ceftazidime alone, 99 percent were alive at 72 hours and 98 percent were alive when the neutropenia resolved, as compared with 100 percent and 98 percent, respectively, of those given combination therapy. Of the patients with documented infection who were given ceftazidime alone, 98 percent were alive at 72 hours and 89 percent when the neutropenia resolved, as compared with 98 percent and 91 percent, respectively, of those given combination therapy. The majority of episodes of documented infection in both treatment groups necessitated additional antimicrobial treatment or other modifications of the initial regimen, as compared with only 22 percent of the episodes of unexplained fever. We conclude that initial single-agent therapy with certain beta-lactam antibiotics is a safe alternative to standard combination antibiotic therapy, although patients with documented infection or protracted neutropenia are likely to require additional or modified treatment.

Abstract

Tremendous progress has been made in the treatment of childhood cancers. Certain hematologic malignancies have an impressive cure rate with the current intensive antineoplastic treatment regimens. There is optimism that the treatment of children who have advanced stage solid tumors with intensive, multimodality therapy may improve their chances for long-term survival. These treatment programs, though potentially curative, are highly toxic, with severe myelosuppression and damage to other organ systems. An awareness of these potential toxicities, an understanding of how to prevent or minimize certain problems, and the ability to treat those complications which do arise are all essential to the successful management of childhood cancer.

IS THERE A ROLE FOR MONOTHERAPY WITH BETA-LACTAM ANTIBIOTICS IN THE INITIAL EMPIRICAL MANAGEMENT OF FEBRILE NEUTROPENIC CANCER-PATIENTSJOURNAL OF ANTIMICROBIAL CHEMOTHERAPYHathorn, J. W., Pizzo, P. A.1986; 17: 41-54

Abstract

In empirical antimicrobial chemotherapy for febrile neutropenic cancer patients, drug combinations are commonly used, and aminoglycosides are usually included for their excellent activity on Gram-negative organisms and for potential synergism. However, new beta-lactams have at least as good a spectrum and in many ways better pharmacology. More Gram-positive infections are now being reported and the sensitivity of the causative organisms varies. This provides reasons for examining alternatives to aminoglycosides, and the use of monotherapy. Clinical results suggest that the emergence of resistance may be a problem with ureidopenicillins used alone, and that double beta-lactams may be as good as but not better than standard regimens. New cephalosporins have been used alone in 14 trials (not all of them well designed) with results as good as those of standard regimens in many, although superinfection with resistant organisms has been a problem in some. It is possible that early supplementation, with aminoglycosides, of empirical monotherapy with such agents as ceftazidime may solve some of the problems posed by resistant organisms.

Abstract

A significantly greater prevalence of interstitial pulmonary infiltrates and Pneumocystis carinii pneumonitis occurred on one arm of a randomized study comparing ProMACE-CytaBOM (prednisone, methotrexate with leucovorin, doxorubicin, cyclophosphamide, etoposide; cytarabine, bleomycin, vincristine, methotrexate with leucovorin) to ProMACE-MOPP (ProMACE, mechlorethamine, vincristine, prednisone, procarbazine) chemotherapy in patients with lymphoma. Of the 37 patients receiving ProMACE-CytaBOM, 13 (35.1%) developed an interstitial pulmonary infiltrate compared with 3 of 32 (9.4%) patients receiving ProMACE-MOPP (p2 = 0.02). Of the 13 patients receiving ProMACE-CytaBOM who had infiltrates, open lung biopsy in 7 showed P. carinii; 5 others had clinically suspected P. carinii pneumonia, and 1 had blastomycosis. No patient receiving ProMACE-MOPP had documented or suspected P. carinii pneumonia. Of patients with infiltrates, 3 of 13 on ProMACE-CytaBOM but 0 of 3 on ProMACE-MOPP died. Two other patients on ProMACE-CytaBOM who had P. carinii pneumonia died. Groups did not differ in predisposing risk factors or patient history. The exact cause for the increased prevalence of P. carinii infection in patients receiving ProMACE-CytaBOM was not ascertained. These data emphasize that new drug regimens may lead to unanticipated complications.

Abstract

The risk of infectious complications ranges from 9 to 80% depending on patient population and definition of catheter-related infection. In the vast majority of these patients, those infections can be treated successfully without catheter removal. The major exceptions to this guideline are patients with significant exit site or tunnel infections or with fungal isolates. Because the majority of those infections are caused by Gram-positive organisms such as S. epidermidis or S. aureus that have variable sensitivities to the antistaphylococcal penicillins, intravenous vancomycin along with gentamicin should be administered empirically until culture results are available. It appears to be unnecessary to remove the Silastic catheter automatically just because the patient is febrile, particularly if there is no microbiological evidence that the catheter is the source of the fever. Quantitative blood cultures drawn through the catheter and from a peripheral vein may lead to a better understanding of the role the catheter plays in the septic episodes in these patients but has yet to be definitive in identifying patients who absolutely require catheter removal to cure their infection. Surveillance cultures have not proved helpful in defining an "at risk" group for catheter-related infection and, due to cost and possible added risk of inducing an infectious complication, should not be routinely performed outside of an investigational setting. Instruction of patients in proper catheter care both before and after placement is of critical importance. To date there is no proved standard of catheter care and maintenance. There is a need for careful investigation in this area. We recommend that routine handling of the catheter be done with aseptic technique, which usually requires use of Betadine swabs when manipulating the catheter tip and use of a sterile dressing (e.g. E. Med IV Strip) or Op-Site (a transparent occlusive dressing) at the exit site. Continued dressings with either daily, every other day or biweekly changes may protect the catheter from gross contamination but do not protect it from catheter-associated infections. Controlled studies are needed to compare the numerous methods of postplacement catheter management and to determine the rate of infectious complications with the recently available double and triple lumen Silastic catheters and the subcutaneous implantable port-type catheters. We are presently pursuing such an investigation.

Abstract

Thirteen years of treating more than 2,950 patients at the National Institute of Dental Research clinic have shown that a variety of potential oral sequelae associated with cancer therapy can be prevented, reduced in severity, or palliatively alleviated when the dental team has an opportunity to participate in the patient's care. The keystone of this success is based on early referral of the patient for dental consultation, treatment before the initiation of cancer therapy, and a well-defined orientation program to inform patients and their families about the difficulties they may experience. Meticulous attention to oral microbial control, prophylactic use of fluoride gels, and palliative treatment of soft tissue lesions may significantly reduce the oral morbidity associated with radiation and cytotoxic chemotherapy. Diligent personal oral health care and frequent dental recall appointments are recommended for the remainder of the patient's life. It has been our experience that patients who are not followed closely after irradiation therapy have an increased incidence of caries as a result of noncompliance with preventive regimens. The ethical and medicolegal responsibility to fully inform the patient of these recommendations lies with both the medical and dental personnel at the facility providing the radiation-chemotherapy service. The general dentist shares the responsibility for continuity of long-term oral health care.

Abstract

To address the problem of drug dosage as a limiting factor for successful chemotherapy, seven patients with Stage IV neuroblastoma were treated with very high dose cyclophosphamide with imidazole carboximide (DTIC) and vincristine sulfate in conjunction with intensive supportive care. None of the patients experienced a complete response. The major toxicity was myelosuppression, complicated by significant infections. Toxicity was significantly more severe in this study than in similar regimens using these three drugs at conventional doses. Although the number of patients in this study was small and most had received prior therapy, our data do not support the efficacy of very high dose cyclophosphamide in the treatment of Stage IV neuroblastoma.

Abstract

The authors discuss the epidemiology, pathology, clinical presentation, and treatment of rhabdomyosarcoma as well as some of the less common sarcomas of childhood and adolescence. Special focus is placed on making careful histopathologic distinction between entities and on clearly recognizing distinct clinical syndromes.

Abstract

Diffuse pulmonary infiltrates and acute respiratory compromise frequently occur in patients with cancer who are undergoing chemotherapy, and treatment remains controversial. We initiated a prospective randomized trial in 22 nonneutropenic patients to compare the efficacy of immediate open lung biopsy with that of empirical trimethoprim-sulfamethoxazole and erythromycin therapy with delayed open lung biopsy if no clinical improvement occurred after 4 days of therapy. Diagnoses included non-Hodgkin's lymphoma (15 patients), T-cell lymphoma (2), acute lymphoblastic leukemia (3), Hodgkin's disease (1), and breast cancer (1). The median age was 40 years, and fever (18) and tachypnea (13) were the most frequent signs. Median room air arterial oxygen tension in 18 hypoxic patients was 53 mm Hg; 19 patients had diffuse pulmonary infiltrates. Eight of the 10 patients randomized to empirical antibiotic therapy showed improvement after 4 days. The 2 patients whose condition did not improve and who underwent delayed open lung biopsy had Pneumocystis carinii pneumonia. One of them did show improvement, and the other died of respiratory failure. Time to clinical resolution in the 9 surviving patients was 14 days; 4 required prolonged ventilation (longer than 24 hours). Findings for the 12 patients randomized to immediate open lung biopsy were P. carinii pneumonia in 7 and nonspecific pneumonitis in 5; there were 3 deaths related to open lung biopsy. Time to resolution in the surviving patients was 13 days for those with P. carinii pneumonia and 5 days for those with nonspecific pneumonitis; 7 required prolonged ventilation.(ABSTRACT TRUNCATED AT 250 WORDS)

Abstract

Infectious complications are a frequent cause of morbidity and, at many centers, the major cause of death in patients with cancer. The increased risk and severity of infectious sequelae result from profound alterations in normal host defenses that occur secondary to the underlying malignancy and the treatment thereof. During the last decade, early empiric antibiotic therapy has become standard practice in the initial management of febrile granulocytopenic patients and has contributed significantly to the improved outcome among patients undergoing cancer therapy. Although early death due to unsuspected or inadequately treated bacterial infection has been largely overcome, new problems--also with life-threatening implications--have emerged. As the use of cancer chemotherapy continues to increase, new populations of patients are being placed at increased risk of infection. Defining the host and environmental factors that contribute to this risk assumes central importance for delineating those patients who require the most intense surveillance. Changing medical practices (e.g., increased use of indwelling catheters) have contributed to the emergence of new pathogens. Recent drug developments (e.g., the third-generation cephalosporins and extended-spectrum penicillins) offer new treatment options, as well as generate controversy and confusion. For example, authorities disagree on the optimal duration and modifications in treatment that are required by cancer patients who remain granulocytopenic and who thus are at continued risk of multiple infectious episodes or superinfections. A question of current interest is whether combination therapy with synergistic agents is important in light of the development of the third-generation cephalosporins and extended-spectrum penicillins. Several of these new antibiotics have an exceedingly broad spectrum of activity that includes Pseudomonas aeruginosa, as well as Enterobacteriaceae, Serratia, Citrobacter, indole-positive Proteus, and anaerobes (including Bacteroides fragilis). However, the third-generation cephalosporins are not as active against staphylococci and streptococci as are the first-generation cephalosporins, and none is effective against enterococci. Nonetheless, these agents achieve serum levels that can be 10 to 100 times greater than the minimal inhibitory and bactericidal concentrations of gram-negative bacteria, raising the possibility that these drugs might be effective as single agents. The advantages of the third-generation cephalosporins are their minimal toxicity and long serum half-lives.(ABSTRACT TRUNCATED AT 400 WORDS)

Abstract

Evaluation of a commercially available lysis-centrifugation blood culture system (Isolator, DuPont Co., Wilmington, Del.) and a lysis-filtration blood culture system for 3,111 cultures showed that both methods had comparable recoveries (73 and 68%, respectively) of significant aerobic and facultatively anaerobic isolates. The unvented conventional blood culture bottle had a recovery rate of 59%. Although the lysis-centrifugation and lysis-filtration systems had comparable recoveries of pathogens, the lysis-centrifugation system had the advantage of having colonies immediately available for further testing. The contamination rate with the lysis-centrifugation system was 3%, compared with 6% with the lysis-filtration system and 0.4% with brain heart infusion.

Abstract

Oral trimethoprim-sulfamethoxazole (Bactrim) plus erythromycin (TMZ-E) was tested versus placebo (P) as prophylaxis for bacterial infection in a randomized, double-blind trial in adult cancer patients receiving cytotoxic chemotherapy expected to result in significant neutropenia. The incidence of adverse reactions attributable to TMZ and/or E was higher in drug-treated episodes (18 of 28 vs 3 of 29 for P, P less than 0.0005) resulting in poorer compliance. The incidence of fever was not significantly different between episodes treated with TMZ-E (18/27) and those treated with P (17/29), nor was there a significant difference in the median interval between the onset of neutropenia and the onset of fever. However, 14 of 18 fevers in TMZ-E recipients were without a documented infectious source compared with only 6 of 17 in P recipients (P less than 0.05). The same patterns were apparent even when episodes in which compliance with the regimen was either excellent or good were considered separately. There was no significant difference in the number of deaths from infection between TMZ-E and P recipients (3/27 vs 1/29). It is concluded that TMZ-E prophylaxis is of no practical benefit, may mask the cause of infection in febrile neutropenic cancer patients, and is associated with substantial toxicity.

Abstract

A prospective, randomized study was performed to evaluate the use of total parenteral nutrition (TPN) in a group of young patients receiving aggressive chemotherapy for metastatic or locally recurrent sarcomas. Fourteen patients were randomly selected to receive TPN and 18 to receive conventional oral nutritional support (CN). During the study period (from first dose of chemotherapy to recovery from myelosuppression), the TPN patients received between 1020 and 2100 calories/m2/day (median 1650) and between 5.3 and 12.4 gmN/m2/day (median 8.9), while the CN patients received between 380 and 880 calories/m2/day (median 685) and between 0.0 and 3.7 gmN/m2/day (median 1.5). The mean daily nitrogen balance during the study period for the TPN group (-3.0 to + 1.3 gmN/m2/day, median -0.7) was significantly higher (p = 0.005) than that of the CN group (-6.2 to -0.7 gmN/m2/day, median -2.6). Serum protein levels (albumin, total protein, and transferrin) did not differ between the two treatment groups. The proportion of patients responding to therapy and the long-term survival rates were similar in the treatment groups. Thus despite established improvement in nitrogen balance, no survival or therapeutic advantage was demonstrated for the adjuvant parenteral nutrition group. Further studies of the role of parenteral nutrition as an adjuvant to cancer chemotherapy are needed to determine which populations of patients will benefit from its use.

Abstract

During a 5 1/2-year period, 34 of 829 episodes of granulocytopenia during which broad spectrum antibiotics were being administered for fever and/or infections were complicated by the development of new pulmonary infiltrates. In 12 patients the infiltrates were due to fungal pneumonia, while in 6 patients the infiltrates were due to a variety of other causes. In the remaining 16 cases the etiology of the infiltrates was not determined. Time to development of infiltrate, radiographic appearance of the infiltrate, patient temperature and absolute granulocyte count failed to predict the etiology of the infiltrate. Conversely, development of the infiltrate or its radiographic progression in the absence of bone marrow recovery correlated significantly with the diagnosis of fungal pneumonia. While empiric alterations of antibiotics at the time that the infiltrate appeared were not associated with improved survival, the early use of amphotericin B was associated with a significant decrease in fatal fungal pneumonia. We suggest that the diagnostic and therapeutic approach to the febrile, granulocytopenic patient who develops a new pulmonary infiltrate while receiving broad spectrum antibiotic therapy may be guided by the state of marrow recovery at the time of infiltrate appearance. Patients developing an infiltrate coincident with granulocyte recovery may be managed conservatively while patients whose infiltrate develops or progresses in the absence of granulocyte recovery should be considered to be at high risk for fungal pneumonia and if possible undergo a diagnostic lung biopsy and/or empiric antifungal therapy.

Abstract

Clinical features of 49 episodes of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome were compared with those of 39 episodes in patients with other immunosuppressive diseases. At presentation patients with the syndrome were found to have a longer median duration of symptoms (28 days versus 5 days, p = 0.0001), lower mean respiratory rate (23.4 versus 30, p = 0.005), and higher median room air arterial oxygen tension (69 mm Hg versus 52 mm Hg, p = 0.0002). The survival rate from 1979 to 1983 was similar for the two groups (57% and 50% respectively). Patients with the syndrome had a higher incidence of adverse reactions to trimethoprim-sulfamethoxazole (22 of 34 versus 2 of 17, p = 0.0007). Survivors with the syndrome at initial presentation had a significantly lower respiratory rate, and higher room air arterial oxygen tension, lymphocyte count, and serum albumin level compared to nonsurvivors. Pneumocystis carinii pneumonia presents as a more insidious disease process in patients with the syndrome, and drug therapy in these patients is complicated by frequent adverse reactions.

LIMITATIONS OF CURRENT ANTIMICROBIAL THERAPY IN THE IMMUNOSUPPRESSED HOST - LOOKING AT BOTH SIDES OF THE COINAMERICAN JOURNAL OF MEDICINEPizzo, P. A., Young, L. S.1984; 76 (3A): 101-110

Abstract

During the last twenty years there have been considerable advances in the antimicrobial management of the immunosuppressed host. These include the development of antibiotics with broad-spectrum and high bactericidal activity along with the appreciation of the importance of promptly initiating empiric antibiotic therapy when the granulocytopenic patient becomes febrile and continuing them (in some cases with empiric antifungal therapy) until the resolution of granulocytopenia. Nonetheless, infection still remains a major cause of death in compromised hosts and a number of limitations of therapy persist. Included are a limited repertoire of drugs active against fungi (particularly Aspergillus) as well as certain viruses (for example, cytomegalovirus) and the inability to eradicate certain sites of infection (for example, Pseudomonas pneumonia) even with effective agents. Current investigations are focused on developing new antimicrobial agents as well as methods to improve the altered host defenses of immunosuppressed patients, both as adjuvants to therapy and, eventually, as a means to prevent infectious complications.

Abstract

The principles for management of infectious complications in cancer patients are continuing to evolve. The critical element includes the prompt institution of broad-spectrum antibiotic(s) empirically when granulocytopenic patients become febrile and continuation and modification of the regimen in patients with persistent fever and granulocytopenia. The view is presented that antibiotics provide systemic prophylaxis as well as therapy in persistently granulocytopenic patients and that they should be continued until all signs of infection have cleared or the granulocyte count has recovered. Such aggressive therapy, supplemented by continued evaluation and monitoring of the patient, can significantly reduce infection-relation morbidity and mortality.

Abstract

We studied the effect of total parenteral nutrition on recovery from myelosuppression in patients receiving intensive chemotherapy. Twenty-seven patients (ages 11 to 33 years) with locally recurrent or metastatic Ewing's sarcoma, rhabdomyosarcoma, or osteosarcoma were randomly selected to receive either conventional oral nutrition or total parenteral nutrition concurrently with intensive chemotherapy. The control group (15 patients) received significantly fewer calories (range 380 to 880/m2 per day, median 685 versus range 1,020 to 2,100 median 1,650) and less nitrogen (0-3.7 g/m2 per day, median 1.5 versus range 5.3 to 12.4, median 8.9) than the group receiving total parenteral nutrition (12 patients). Assessment of recovery from myelosuppression was based on the length of time the absolute granulocyte count was below 500/mm3, the length of time the platelet count was below 40,000/mm3, the number of days the platelet count was below 20,000/mm3, and the number of blood transfusions required. There was no statistical difference in any of the parameters evaluated between the group that received total parenteral nutrition and the control group (p less than 0.05); granulocyte and platelet recovery and the difference in transfusion requirements favored the control group with marginal statistical significance (p = 0.05). The frequency of clinical infections was similar in the patients receiving total parenteral nutrition (five of 12) and in those receiving conventional oral nutrition (five of 15). Thus, although total parenteral nutrition could be safely administered in this severely myelosuppressed population, no benefit could be defined in recovery from bone marrow suppression or frequency of clinical infections.

Abstract

Twenty-four high-risk Ewing's sarcoma patients were treatedf on an intensive combined modality protocol including low-dose fractionated total body irradiation (TBI) and autologous bone marrow infusion (ABMI). Twenty patients (83%) achieved a complete clinical response to the primary and/or metastatic sites following induction therapy. The median disease-free interval was 18 months, and nine patients remain disease-free with a follow-up of 22 to 72 months. Local failure as a manifestation of initial relapse occurred in only three patients (15%), each having synchronous distant failure. Eight patients failed initially with only distant metastases, usually within 1-2 years following a complete clinical response. Two patients with a single metastasis were again rendered disease-free and remain free from second relapse with 18 and 30 months follow-up. No other relapsed patient was able to be rendered disease-free, and most died of progressive disease within 6 to 12 months of relapse. Two patterns of granulocyte recovery following consolidative therapy (include TBI) and ABMI were recognized. Seventeen patients reached a total granulocyte count of >500 cells/mm3 within 4 weeks of ABMI (early graulocyte recovery), while seven patients required >4 weeks from ABMI (late granulocyte recovery). The time of platelet recovery (>50,000/mm3) was different for the groups with early and late granulocyte recovery (25 days vs. 54 days, p 1/2 pelvis prior to bone marrow storage. Patients with late recovery did not tolerate maintenance chemotherapy. However, there was no difference in disease-free and overall survival, when compaing the groups with early and late granulocyte recovery. We conclude that these high-risk Ewing's sarcoma patients remain a poor-prognosis group in spite of intensive combined modality therapy include low-dose TBI. The control of microscopic systemic disease remains the major challenge to improving the cure rate. A new combined modality protocol with high-dose 'therapeutic' TBI (800 rad/2 fractions) is being used and the protocol design is outlined.

Abstract

In an attempt to reduce the incidence of fever and infection, we randomized patients with cancer to receive trimethoprim/sulfamethoxazole plus erythromycin (TMP/SMX + E) versus placebos after each cycle of chemotherapy (no crossover) and to continue until granulocytopenia (polymorphonuclear leukocytes less than 500/mm3) resolved or the patient became febrile. We evaluated 541 episodes (150 patients); 249 episodes (77 patients) with TMP/SMX + E and 292 episodes (73 patients) with placebos. The patients' median age was 17 years. Thirty percent of the patients had leukemia, 23% had lymphoma, and 47% had solid tumors. Compliance with prescribed medication was prospectively rated as excellent in 60.6%, good in 11.7%, poor in 11.1%, and unknown in 16.6%; compliance was better for the placebo group (P = 0.001). The overall incidence of fever or infection was 22.1% for the TMP/SMX + E group versus 26.9% for the placebo group. When only episodes with excellent compliance in which granulocytopenia was documented were compared, the incidence of fever or infection was 18.1% for the TMP/SMX + E group vs 32.2% for the placebo group (P = 0.009), with bacterial infection occurring in 3.8% of the TMP/SMX + E group vs 11.9% of the placebo group (P = 0.019), and unexplained fever in 10.5% of the TMP/SMX + E group vs 19.6% of the placebo group (P = 0.037). Patients with good or poor compliance showed no significant benefit from the TMP/SMX + E, and patients with excellent compliance did best, regardless of whether they were receiving antibiotics or placebos, suggesting that patient compliance is an important independent variable. The incidence of fever or infection was significantly lower for patients with leukemia with excellent compliance who received antibiotics (P = 0.037) than for patients with lymphomas or solid tumors. Oral antibiotic prophylaxis reduced the incidence of fever and infection in some granulocytopenic patients, but the benefit was limited and restricted to patients whose compliance was complete.

Abstract

Nutritional intervention in the cancer patient [e.g., total parenteral nutrition (TPN)] might improve durable survival because of increased tolerance to aggressive tumor therapy. To determine whether this assumption is correct, 42 patients with diffuse histiocytic lymphoma were induced with prednisone, high-dose methotrexate, Adriamycin, cyclophosphamide, and VP-16 (ProMACE). Nitrogen mustard-vincristine-procarbazine-prednisone (MOPP) consolidation was then used, followed by late intensification with ProMACE. Patients were selected randomly to receive adjuvant TPN or a standard diet during ProMACE-MOPP treatment. While TPN patients had a greater median weight gain than did control patients, lean body mass and degree of myelosuppression did not improved as a consequence of TPN. There was no significant difference in tumor response or survival between TPN and control patients, whether or not the patients were initially malnourished. In a second trial, 32 young patients with metastatic or other poor-prognosis sarcomas were randomly allocated to receive TP or a standard diet as an adjunct to one very intensive course of combination chemotherapy or chemotherapy plus total body irradiation; autologous marrow transplantation was used with gain than did controls but remained in a negative nitrogen balance. Response rates and median durable survival did not differ between the two groups. In both trials, the maximum nutritional support permitted by currently available technology was offered. Thus, the limiting factor may not be nutritional status but rather the intrinsic biology of the tumors and the limitations of their response to current therapy. In in vitro studies of the possible influence of nutrition on cancer treatment, we have compared sublines of P388 murine leukemia cells which are sensitive or resistant to Adriamycin. The difference in drug sensitivity correlated with differences in lipid composition, with more intracellular lipid, and with greater membrane rigidity in the resistant cells. Resistant cells have a relatively poor transport of drug into the cell; moreover, intracellular Adriamycin is sequestered in lipid depots away from DNA. These results suggest one possible relationship between nutritional phenomena and drug sensitivity.

Abstract

An aggressive surgical approach was used in the diagnosis and treatment of seven immuno-incompetent patients who presented with focal thoracic mass lesions. In five of the seven patients, minor diagnostic procedures had failed to provide a diagnosis. All seven patients were subjected to exploratory thoracotomy with resection and/or drainage of the involved area. Two patients had parenchymal masses, two had lung abscesses, two had empyemas with trapped lung, and one had a bronchial fistula. An accurate diagnosis and full resolution of the intrathoracic process was obtained in all patients. There was little morbidity and no operative mortality in this series. Resection of focal thoracic lesions in immuno-incompetent patients combines accurate diagnosis with precise therapy and is well tolerated in this high risk group of patients.

Abstract

The organisms designated as Center for Disease Control group JK are gram-positive rods that have previously been described as causing serious infection in compromised hosts. Four years of hospital experience with this group of organisms in Clinical Center patients was reviewed. Studies were also undertaken on specific wards to determine frequency of occurrence and distribution patterns. Inguinal cultures taken on two wards showed that 30 to 35% of patients were colonized with group JK and that newly admitted patients may already be colonized at the time of admission. Colonization was shown to persist for weeks and sometimes months. Isolates obtained throughout the hospital were predominantly from cancer patients, particularly in wounds, abscesses, and drainage sites. Most blood isolates were from granulocytopenic patients with hematological malignancies.

Abstract

Epstein-Barr viral (EBV) DNA is nearly always detectable in African Burkitt's lymphoma (BL) but is infrequently found in the histologically indistinguishable American BL. We have derived a tumor cell line from a patient with American BL which produces EBV, and we have compared this virus isolate [JLP(c)] with African BL EBV. The American JLP(c) virus immortalizes human umbilical cord lymphocytes in vitro, and its DNA is indistinguishable from African BL EBV DNA by nucleic acid hybridization and preliminary restriction endonuclease cleavage analysis.

Abstract

While Epstein-Barr viral (EBV) DNA is nearly always detectable in African Burkitt's lymphoma (BL), the relatively low frequency of BL in EBV-positive African children and the infrequent finding of EBV in American BL suggest that other cofactors may contribute to the malignant transformation. Among these possible cofactors are type C oncornaviruses. To evaluate this possibility, we screened the cellular DNA from 16 lymphomas (2 African, 14 American) and the DNA from 20 lymphoma-derived cell lines (4 African, 16 American) with a radiolabeled viral DNA probe from EBV and two oncornaviral probes (murine amphotropic 1504A virus and simian sarcoma virus). The radiolabeled EBV DNA probe hybridized with 18 of 36 tumor or cell line DNA's. Only 2 of 11 American BL tumors contained detectable EBV sequences. However, the cell lines derived from three EBV-negative tumors converted in vitro to EBV positivity, suggesting that some of the tumor cells could be infected with EBV. In contrast, none of the tumors or the cell lines derived therefrom hybridized with either the 1504A or the simian sarcoma virus probes, decreasing the likelihood that type C viruses are cofactors with EBV.

Abstract

Amphotericin B is used increasingly in high-risk patients with profound neutropenia and suspected sepsis. We have observed serious pulmonary reactions characterized by acute dyspnea, hypoxemia, and interstitial infiltrates on chest films in patients receiving amphotericin B and leukocyte transfusions. We reviewed 6 1/2 years of experience at the National Institutes of Health to determine whether this combination was associated with pulmonary toxicity not characteristic of either therapy alone. Amphotericin was used during 22 of 57 leukocyte-transfusion courses. Acute respiratory deterioration occurred during 14 (64 per cent) of these courses but in only two (6 per cent) of 35 courses without amphotericin (P less than 0.01). In seven cases, respiratory deterioration began during or immediately after amphotericin infusion, and it contributed to death in five patients. Diffuse intraalveolar hemorrhage was found when lung biopsy or autopsy was performed. Acute respiratory deterioration was not observed in comparably neutropenic patients given amphotericin but not leukocyte transfusions during the same period. It was mot common when amphotericin was begun with or after institution of daily leukocyte transfusions. Leukocyte transfusions may cause changes in the lungs that amplify the acute toxicity of amphotericin, thereby permitting severe pulmonary reactions.

Abstract

Sixteen lymphoid cell lines were derived from patients with undifferentiated lymphoma of Burkitt's or non-Burkitt's type. They were obtained directly from tumor biopsies, from serous effusions, or from bone marrow. In 10 of the cell lines, the Epstein-Barr virus (EBV) nuclear antigen (EBNA) was undetectable; the remaining 6 lines were EBNA-positive (EB-pos). Of the 16 lines, 15 were aneuploid, with detectable chromosome "14q+ markers (11 had +8;14 translocations). These 15 lines, which included the EBNA-negative (EB-neg) lines, were believed to be of tumor cell origin. The remaining line consisted predominantly of diploid cells derived from normal lymphocytes, but some cells of tumor origin were present. Four EB-pos cell lines derived from EB-neg tumors had an aneuploid karyotype consistent with an origin from tumor cells (including no.8;14 translocation in two), which suggested that either tumor cells were infected with EBV in vitro or a tiny fraction of EB-pos tumor cells (or potential tumor cells) present in vivo gave rise to the predominant cell of the line. EB-neg B-cell lines and EB-pos cell lines established from undifferentiated lymphomas differed greatly. EB-neg lines had consistently smaller electronic mean cell volumes and narrow-angle light scatter than did EB-pos lines. This finding correlated with a lower nuclear:cytoplasmic ratio in EB-pos lines. EB-neg lines also had higher saturation cell densities than did EB-pos lines under standard culture conditions. The data indicate either that EBV influences the morphologic and physiologic characteristics of lymphoid cell lines or that EB-neg B-cell lines and EB-pos cell lines are derived ultimately from different lymphocyte subpopulations or that both may apply.

Abstract

Seventy-eight pediatric cancer patients were treated for gram-positive bacterial septicemia during a 10-year period (1968-1977). Sixty-one (78%) of the patients were granulocytopenic (PMNs less than 500/mm3) at the onset of the septic episode. All the patients whose granulocytopenia resolved (PMNs greater than 500/mm3) within one week of therapy recovered without sequelae. However, 7 of 15 patients (47%) who remained granulocytopenic for more than 7 days and who were treated with a single antibiotic developed a second sepsis with a gram-negative organism. In contrast, second infections were not observed in 24 patients with PMNs less than 500/mm3 for more than 7 days who were treated with broad spectrum antibiotics (p less than 0.002), suggesting that a broad-spectrum antibiotic regimen may be preferable when a cancer patient has prolonged granulocytopenia.

Abstract

Fifteen of 16 lymphoma-derived cell lines and the Faji and P3HR1 cell lines were characterized with regard to certain surface markers, particularly immunoglobulins, complement receptors, Epstein-Barr virus (EBV) receptors, and Fc receptors. Ten lines positive for EBV nuclear antigen (EB-pos) were stained weakly or not at all by antihuman immunoglobulin fluorescein isothiocyanate conjugates, whereas EBV nuclear antigen negative (EB-neg) cell lines stained brightly. EB-pos lines frequently manifested Fc receptors, particularly for 7S antibody, whereas EB-neg lines did not. Receptors for the C3b component of complement and for EBV, which correlated significantly with each other, were expressed to a much lesser extent by EB-neg lines than by EB-pos lines. These findings are pertinent to an understanding of the infrequent association of this virus with American undifferentiated lymphomas of the Burkitt's and non-Burkitt's types.

Abstract

The deleterious effects of separation have been demonstrated in experimental animal studies and in naturalistic case studies of children. In this study extensive observational and physiological records were obtained on four preschool children who were receiving chemotherapy for childhood cancer. The findings generally parallel those reported in the subhuman primate literature. The children's behavior followed a sequence of agitation followed by behavioral depression. The findings underscore the seriousness of parent-child separation and the need to develop intervention strategies to ameliorate these deleterious effects.

Abstract

Some of the current experimental approaches to the treatment of CNS leukemia are reviewed. While small animal models have provided a basic understanding of the pathophysiology of meningeal leukemia, large animal models, particularly the subhuman primate, allow a more detailed examination of the complex dynamics of CNS pharmacokinetics. Principles derived from these models have provided a rational basis for the development of new approaches to the treatment of meningeal leukemia in man.

Abstract

While major advances have been made in the treatment of acute leukemia, complications of therapy are significant. One of the most worisome complications is the neurotoxicity which is related to both central nervous system prophylaxis (cranial irradiatif neurotoxicity may be acute or delayed, and may range in severity from mild headaches ann of treatment-related neurotoxicity is important since this may permit amelioration of otherwise irreversible neurological sequelae in some patients. We review the clinical, phyh irradiation and chemotherapy, and offer recommendations for monitoring, evaluating and treating patients with potential or proven neurotoxicity.

Abstract

Seventy episodes of Staphylococcus aureus sepsis occurring over a nine-year period in pediatric cancer patients are reviewed. Prominent findings at the time of diagnosis included fever, granulocytopenia, and active malignancy. Probable or suspected sites of primary infection were present in 40 episodes (57%). Serious direct complications of staphylococcal sepsis included only three cases of pneumonia and one of myositis. However, second infections by other organisms developed in 16 episodes (24%), resulting in nine nonstaphylococcal infectious deaths during therapy. Endocarditis and osteomyelitis never occurred in this group of patients. The median duration of antistaphylococcal therapy was 15 days.

Abstract

A case of lactic acidosis associated with the administration of hypertonic glucose to a patient with a bulky undifferentiated carcinoma is presented. Characteristic alterations in amino acid concentrations were observed during the period of lactic acidosis. Resolution of the metabolic abnormalities were seen with discontinuation of glucose infusion. Short-term glucose infusion in a 90 minute iv glucose tolerance test resulted in an increase in serum lactate and appropriate changes in serine, ornithine, taurine, alanine, and arginine despite normal hormonal responsiveness.

Abstract

Eleven patients with metastatic osteogenic sarcoma were treated with cyclophosphamide, adriamycin, and, in some cases, high-dose methotrexate. In the event of metastatic progression, the dose of cyclophosphamide was escalated by increasing the number of consecutive daily infusions (dose, 45 mg/kg/day). The results indicate that metastatic osteogenic sarcoma is marginally responsive to adriamycin and cyclophosphamide but rarely responsive to high-dose methotrexate as administered in this trial. The response of metastatic lesions was not improved by escalating the dose of cyclophosphamide.

Abstract

Fourteen patients with American Burkitt's lymphoma resistant to conventional chemotherapy were treated with high-dose combination chemotherapy and intensive supportive care. Four patients died shortly after chemotherapy, 3 of an acute carditis. All ten remaining patients demonstrated tumor regression and 3 remain in prolonged complete unmaintained remission 29+, 19+, and 9+ months after treatment. These findings demonstrate that high-dose chemotherapy will benefit some patients with Burkitt's lymphoma unresponsive to conventional chemotherapy, but the medullary and extramedullary toxicity of this treatment strategy remains a formidable obstacle.

Abstract

Alpha-hemolytic Streptococci were associated with 29 episodes of sepsis (12 polymicrobial) in 27 patients with cancer during a nine year period. Only two patients had dental manipulation prior to the onset of sepsis, but each had received chemotherapy and 75% were granulocytopenic (PMN less than 500/mm3) at the time of the infection. None of the patients developed bacterial endocarditis. Unlike the normal host in whom a transient bacteria with alpha-hemolytic Streptococci may occur following dental extraction or periodontal procedures, the cancer patient is at risk for more clinically significant sepsis. This risk is probably related to the presence of chemotherapy-induced oral mucusitis and granulocytopenia, and our results suggests that isolation of alpha-hemolytic Streptococci in febrile cancer patients should not be dismissed as a contaminent.

Abstract

Two of 27 patients treated with intraventricular chemotherapy via an Ommaya reservoir developed unusual life-threatening complications attributable to the reservoir. In one patient treated for meningeal Burkitt's lymphoma, the cause of death was a large mass of tumor cells growing around the cannula. Also the tip of the cannula was found in the contralateral cerebral peduncle. In the other patient, the tip of the cannula apparently perforated the ventricular wall postoperatively and migrated into the contralateral thalamus. In both cases evidence for methotrexate-associated leukoencephalopathy was present at autopsy. Based on the experience with these two patients, we offer specific recommendations for reservoir insertion and use.

Abstract

Thirty-two asymptomatic patients with acute lymphocytic leukemia, who had received prophylactic cranial radiation (2400 rads) and either intrathecal methotrexate or cytosine arabinoside were studied by computed tomography of the brain 19 to 67 months after initiation of prophylaxis. Seventeen of 32 (53 per cent) had one or more abnormal findings. Dilatation of the ventricles (eight patients) and widening of the subarachnoid spaces (nine patients) were equally distributed among patients in both intrathecal-chemotherapy groups. Areas of decreased attenuation coefficient (hypodense, abnormally radiolucent regions) (four patients) and intracerebral calcification (one patient)--lesions previously described in methotrexate leukoencephalopathy--were found only in those who had received intrathecal methotrexate. Mild central-nervous-system dysfunction was detected in seven patients but did not correlate with the presence of tomographic abnormalities. Nevertheless, these tomographic findings may represent preclinical lesions. The unexpectedly high prevalence of such abnormalities contrasts with the essentially normal tomographic findings in a control group with acute lymphocytic leukemia who received no central-nervous-system prophylaxis. These results suggest that alternative approaches to such prophylaxis be considered.

Abstract

Two patients with acute lymphoblastic leukemia treated on the same protocol became blind during complete remission. Therapy consisted of systemic combination chemotherapy, prophylactic central nervous system irradiation and monthly intrathecal cytosine arabinoside. Eight months after CNS irradiation visual acuity in both patients began to decrease. Meningeal leukemia in the area of the chiasm was suspected but despite additional radiotherapy, steroids and continued intrathecal therapy, both patients were blind within 6 months. Numerous lumbar punctures were negative for leukemic cells. Extensive investigation, including craniotomy in one case, failed to reveal the cause of blindness. Biopsy of the optic nerve in one case was compatible with radiation toxicity. We postulate that potentiation of radiation toxicity to the optic nerves and chiasm by systemic chemotherapy, intrathecal chemotherapy, or both, may have led to blindness. The patients continue in complete hemotologic and CNS remission 12 and 29 months after becoming blind.

Abstract

Twenty-four children (2 to 21 years) diagnosed as having AML from 1969 to 1972 were randomized to receive either a single combination (COMP or PRAVD) or sequential combination chemotherapy (alternating POMP and PRAVD). Seventeen achieved complete remission. Patients who received POMP alone had the longest median duration of remission (1,400 days) compared to PRAVD (395 days) or POMP-PRAVD (270 days); interpretation of this difference is uncertain, since the numbers in each group are small. Fifteen patients have relapsed, four initially with CNS involvement. Successful reinduction was achieved almost exclusively for patients who had initially received POMP. Survival after first relapse was short. Patients less than 16 years had a median survival of 632 days, compared to 285 days for patiens greater than 16 (p less than 0.05). The high initial induction rate in these patients is encouraging, but the duration remission is inferior to that seen in childhood ALL. Moreover, the slope of the relapse curve is continuous over a five-year period with no definite plateau where it might appear that patients are no longer at risk of relapse. Improved methods for the treatment of childhood ALL and adult AML suggest possible new approaches to AML in children, with prophylactic treatment of central nervous system, late intensification, and immunotherapy.

Abstract

During maintenance therapy with intraventricular methotrexate, progressive dementia developed in a child with meningeal leukemia. Cerebrospinal fluid levels of MTX were in the nontoxic range and neurologic evaluation failed to demonstrate anatomic obstruction, infection, or folate depletion. The patient's symptoms gradually resolved when the methotrexate was discontinued, suggesting that methotrexate neurotoxicity may occur in the absence of an elevated CSF concentration of MTX.

Abstract

One hundred children admitted to a hospital over a six-year period with temperatures over 38.5 C for longer than two weeks and of undetermined etiology are reviewed. Fifty-two were infectious (21 presumed viral), 20 collagen-inflammatory, 6 malignancy, 10 miscellaneous, and 12 discharged undiagnosed. Children less than 6 years were more likely to have an infectious etiology while 80% of collagen-inflammatory disease occurred in the group older than 6. The overall mortality (9%) was not age-related. Careful history and physical examinations were helpful but the usual laboratory data (CBC, urinalysis, X-ray) were notably disappointing; however, sedimentation rates and serum protein electrophoresis were often reliable screening tests. Biopsy and laparotomy were less frequently done but when performed yielded productive information. Unusual presentations of common diseases comprised the majority of childhood fevers.